Pulmonary Dendritic Cells

http://www.100md.com 美国呼吸和危急护理医学 2005年第9期

     Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

    ABSTRACT

    Dendritic cells (DCs) are leukocytes that are emerging as chief orchestrators of immune responses. The crucial task of DCs is the continuous surveillance of antigen-exposed sites throughout the body, and their unique responsibility is to decide whether to present sampled antigen in an immunogenic or tolerogenic way. Any misstep can either lead to a flawed immune defense or to allergy, even autoimmunity. It comes as no surprise that the lungs become increasingly the subject of DC-related investigations, as they represent a vast interface between the body and the outer world. This constitutes an enormous challenge for the immune system: "firing up" immune responses inappropriately could have devastating results for the fragile gas exchange structures. Evidence accumulates that DCs play a pivotal role in maintaining the delicate balance between tolerance and active immune response in our respiratory system. The exponentially growing body of DC-related publications is a big challenge. This article aims to provide researchers and clinicians with an up-to-date view on DC biology and its relevance to pulmonary medicine. A developing trend in the field of DCs is the shift from fundamental immunologic research toward exciting clinical insights and applications. For the pulmonary clinician, this heralds the dawn of promising therapies in various domains such as infections, allergy, and cancer.

    Key Words: airway; chemokine; chronic obstructive pulmonary disease; dendritic cell; lymph node

    INTRODUCTION

    The "Sentinel" Paradigm of Dendritic Cell Biology

    The first dendritic cells (DCs) were described by Paul Langerhans in 1868 in the basal layers of the epidermis (eer die Nerven der menschlichen Haut. Virchows Archiv fe pathologische Anatomie und Physiologie, und fe klinische Medicin 1868;44:325eC337). These "Langerhans' cells" displayed a typical dendritic morphology, with long, branched arms interdigitating between surrounding epithelial cells. This peculiar shape prompted Dr. Langerhans to consider these cells as a type of neuron. It took more than a century to generate insights through which DCs were correctly identified as white blood cells related to macrophages and monocytes. Subsequently, DCs were described in all lymphoid organs (1), in the blood (2), in the bone marrow (3), and in several other organs, including the lung (4), gut (5), liver (6), heart (7), kidney (8), and urogenital tract (9). Meanwhile, the crucial role of DCs in the control of immunity started to emerge slowly, thanks in part to a series of seminal articles by Steinman and coworkers in the 1970s (1, 10eC13). It was known that T lymphocytes, the effector "muscles" of the immune response, cannot recognize antigens (e.g., microbes, tumor fragments, or allergens) in their native form. So-called antigen-presenting cells (APCs) are required to first sample and then process antigens into short fragments, which are presented to T cells on major histocompatibility complex (MHC) molecules. In addition, APCs provide "costimulatory" molecular signals that are required to raise T-cell activation above a threshold allowing an active response. Before the era of DCs, the only known professional APCs were the macrophages, monocytes, and B lymphocytes. With time, however, it became clear that the antigen-presenting power of DCs greatly exceeded what was documented so far (14, 15). This appeared to rely on some unique features in the biology of these cells (for a comprehensive review, see Reference 16).

    First, DCs are strategically mobilized to anatomic sites with high antigen exposure (e.g., skin, mucosal surfaces, spleen), thanks in part to their sensitivity to a whole array of chemoattracting inflammatory signals. At this stage, DCs are termed "immature," which implies a high capacity to sense, sample, and process incoming antigen, but a poor ability to stimulate T cells. When antigen exposure is accompanied by so-called danger signals (typically, molecular signatures from pathogens or tissue destruction), DCs undergo a series of dramatic changes, which are defined as "maturation" or "activation" (reviewed in Reference 17). From this point on, the antigen-uptake and antigen-processing function is shut down while large amounts of processed antigen are displayed on cell surface MHC molecules, together with a whole battery of T-cell costimulatory factors. At the same time, DCs become specifically attracted to chemokines emanating from the T-celleCrich areas of local lymphoid organs (this is in sharp contrast to more sedentary sentinel cells, such as macrophages). After migration into the lymph node (LN), DCs induce the proliferation of antigen-specific T lymphocytes, which differentiate into cytokine-producing effector T cells capable of recirculating to the endangered tissues. A summary of this "sentinel" paradigm of DC biology and the molecules generally involved is shown in Figure 1.

    Although it constitutes a very efficient defense system, the sentinel function of DCs carries an inherent danger. Invasion by pathogens is usually accompanied by tissue destruction, and there is a substantial risk that activated DCs might take up and present released self-antigens along the way, leading to the induction of autoimmunity. This is especially worrisome because experimental evidence points to the necessity for maintaining self-tolerance throughout life. Fortunately, it appears that DCs play an active role here as well. Indeed, apoptotic cell fragments originating from normal tissue turnover are continuously taken up and processed by DCs (18eC20). Those "resting" DCs that present self-material and home to the T-cell areas in the steady state lead to the priming of immunosuppressive regulatory T cells or even T-cell deletion (21eC24). Understandably, the role of DCs in the protection against, or the induction of, autoimmunity is currently drawing more and more interest.

    In summary, the DC system of leukocytes has evolved into a fine-tuned, highly sensitive sentinel network capable of both igniting as well as shutting down immune responses as appropriate. This article first provides general notions on DC subsets, where these subsets are found in the lung, and how DCs control the pulmonary immune response. In a second part, we summarize current insights on the possible role of DCs in several major pulmonary pathologies.

    Some of the results of the studies described have been previously reported in the form of abstracts (25, 26).

    Defining Features of the Human DC Family

    Despite the arsenal of techniques available to modern-day researchers, DCs are still difficult to study due to a number of issues, as follows, all of which also apply to the lung:

    DCs are rare cells in situ: they represent at most a few percent of the total cell population in a given organ.

    Isolating DCs from tissue samples easily induces activation artifacts: DCs are exquisitely sensitive to stress signals arising from the environment. Classical methods for extraction of these cells involve a whole sequence of procedures, including enzymatic organ digestion, gradient centrifugations, and/or overnight incubation steps. All these interventions can cloud the original state of the DC in situ.

    In contrast to other leukocytes, DCs cannot be immunophenotypically identified using one single antigenic marker. Human DCs are commonly identified by the abundant expression of MHC class II (HLA-DR is commonly used as a marker) and the absence of T, B, and natural killer cell, monocytic, and granulocytic lineage markers. Mature or activated human DCs are characterized by a further increase of HLA-DR and costimulatory molecules (e.g., CD40, B7-1, B7-2) on their surface. Additional specific markers of mature human DCs are the immunoglobulin superfamily member CD83 (27), the 55-kD actin-bundling protein Fascin (28, 29), and the DC-specific lysosome-associated membrane protein DC-LAMP (30).

    An overview of the human DC family tree, together with typical identifying markers, is shown in Figure 2. Currently, an important distinction is made between two main DC subtypes: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). Human mDCs develop from bone marroweCderived monocytic precursors, whereas pDCs are developmentally related to the lymphoid lineage (31). In addition to differences in identifying markers (32, 33), the most relevant distinction between mDCs and pDCs is functional because these cells are activated by a different set of pathogenic stimuli. This reflects a differential expression of specific Toll-like receptors (TLRs) on both subsets (34).

    TLRs are primitive sensors for "danger signals," which are, for the most part, microbial molecular signatures but also include products released by cell necrosis and extracellular matrix breakdown (reviewed in Reference 35). Human mDCs primarily express TLR2 and TLR4 and become mature in response to LPS and mycobacterial cell wall components. In contrast, human pDCs do not possess LPS-sensing receptors but typically express TLR7 (a target for the immunomodulatory molecule imiquimod) and TLR9 (the receptor for unmethylated microbial DNA sequences). Typically, immature pDCs exposed to viral products secrete massive amounts of type I interferon, indicating that these cells are in fact identical to the long-known natural interferon-producing cell (36). Thus, pDCs first deliver a powerful innate response designed to limit viral replication, after which these cells differentiate into mature DCs capable of triggering an adaptive immune response. In addition to mDCs and pDCs, Langerhans' celleCtype (i.e., intraepithelial) DCs are often considered as a separate DC subset in humans. Their origin and developmental relationship to other DCs is subject to differing views (37eC40). Langerhans' cells (LCs) are typically located above the basement membrane in epithelial layers of antigen-exposed organs and extend long, branched pseudopods between surrounding epithelial cells (41). LCs have specific requirements in terms of hematopoietic growth factors (42), and can be identified by the presence of typical Birbeck granules (tennis racketeCshaped intracellular organelles with unknown function) and a set of markers such as E-cadherin (which anchors LCs to neighboring epithelial cells), CD1a, and Langerin (43). Another subset of DCs are the so-called interstitial-type DCs, first described in the dermis. These share some markers with resident macrophages (e.g., CD68), but in contrast to macrophages, exhibit a potent T-cell stimulatory activity (42). In addition, interstitial DCs appear to be the only DC subset capable of inducing B-cell differentiation and drive humoral immune responses (44).

    DCs OF THE LUNG: LOCALIZATION AND PHENOTYPE

    Sertl and colleagues (4) was one of the first to describe the presence of DCs in the airway epithelium, lung parenchyma, and visceral pleura of human and mouse specimens. These cells displayed a typical dendritic morphology, expressed copious amounts of MHCII on their surface, and acted as potent T-cell stimulators in vitro. Later studies have provided more detail into the features and localization of DCs in the different pulmonary compartments. From a methodologic point of view, immunofluorescent techniques allow identification of pulmonary DCs among low-autofluorescent leukocytes (next to lymphocytes and granulocytes), in contrast to the highly autofluorescent pulmonary macrophages (45eC47). Using this approach, a small number of DCs can be detected in the bronchoalveolar lavage fluid (BALF). A fraction of these cells express LC markers (CD1a, S100) and exhibit potent T-cell stimulatory capabilities in an allogeneic mixed leukocyte reaction (45, 48). A recent study succeeded in distinguishing different DC subsets in human BALF (i.e., an mDC subset; 0.06% of BALF cells) and a pDC subset (0.02%) (49). Within the bronchial epithelium, DCs are found with typical features of LCs, such as the presence of Birbeck granules, the expression of CD1a, and Langerin (Figure 3) (43, 50, 51). Specific tissue preparation techniques applied to rodent specimens have succeeded in visualizing this superficial airway DC network (Figure 4) (52eC54). In the absence of inflammation, DCs are distributed at an average density of several hundred cells per millimeter squared in the large airways, decreasing to less than a hundred DCs per millimeter squared within smaller intrapulmonary airways (52). DCs in the lung parenchyma are present in larger numbers. They are mostly found within interalveolar septa (55). Cochand and coworkers (56) have clearly described the immature character of human lung parenchymal DCs, in terms of low T-cell costimulary molecule expression, the presence of receptors for inflammatory chemokines, and a strong antigen-uptake activity. Recently, our group succeeded in identifying three previously undescribed types of DCs in normal human lung parenchyma: two subsets of mDCs (one, CD11c+/BDCA[blood DC antigen]-1+; the other, CD11c+/BDCA-3+) and one pDC subset (CD11ceC/BDCA-2+) (51). We are currently trying to characterize the functional differences between these subsets, and the impact of lung disease on these cells.

    LUNG DCs AND THE SHAPING OF THE PULMONARY IMMUNE RESPONSE

    A growing body of experimental evidence indicates that the "sentinel" paradigm of DC function applies extremely well to the respiratory system. This implies (1) a constant recruitment of DCs into the lung, (2) a capacity for these cells to sense and capture inhaled antigen, and (3) an efficient transport of processed antigen to the draining pulmonary LNs, where DCs decide which type of immune response will ensue.

    DC Recruitment to the Lung Is Driven by Environmental Stimuli

    Even in the absence of overt inflammation, DCs or their precursors are constantly recruited from the blood into the lung. Holt and coworkers (57) were the first to demonstrate that respiratory tract DCs are continuously replenished by a steady-state bone marrow output. Further studies in animals have shown that the steady-state deployment of the respiratory tract DC network is clearly correlated with age (58): although MHCII+ DCs already colonize the fetal lung mesenchyme, airway mucosal DCs only appear a few days after birth, reaching adultlike density and distribution after weaning. Interestingly, DCs spread in a "wave," which starts at the nasal mucosa and progressively spreads deeper into the trachea, all the way down to the alveolar walls. Also, the degree of maturation or activation seems to correlate with the proximity to the outside environment.

    Not surprisingly, inflammatory stimuli in the inhaled air have a profound impact on these steady-state dynamics. In a series of hallmark experiments, McWilliam and colleagues (59) described how the inhalation of pathogenic material, such as bacteria or viral particles, induced a very rapid influx of DCs into the airways of rats, in some cases peaking already 2 hours after challenge. Remarkably, this DC recruitment was as fast or sometimes ahead of the prototypic neutrophil influx. It was an isolated phenomenon among mononuclear cells because macrophage numbers were not increased and lymphocytes were not present at that time point. This surprising discovery overthrows the classical view of host defense in which a first phase of neutrophilic influx is gradually taken over by a mononuclear infiltrate. It indicates that DC recruitment is an integral part of the early phase of the innate immune response, with the potential to progress toward a powerful adaptive defense.

    Resolution of the inflammation usually restores baseline numbers of pulmonary DCs. However, in some cases, this normalization can be considerably delayed, as observed after Sendai virus infection in rat airways (60), and in a mouse model of respiratory syncytial virus infection in which pulmonary DC numbers were still increased weeks after remission of the acute inflammatory phase (61).

    On a molecular level, isolated respiratory tract DCs were shown to be attracted by a whole array of stimuli, including chemokines, complement cleavage products, and bacterial peptides (62). By far the most studied among these mediators are the chemokines (reviewed in Reference 63). Chemokine concentration gradients elicit a directed cellular movement, a phenomenon known as chemotaxis. In vitro studies show that many cells of the lung produce a wide array of chemokines with a known effect on DCs in general (see Table 1 and References 64eC81), although only a few have been studied in detail with respect to pulmonary DC mobilization. In vivo, different chemokines orchestrate the recruitment of DCs into the lung depending on the inflammatory stimulus present. In a rat model of inhaled heat-killed Moraxella catarrhalis, the phenomenon seemed dependent on the expression of CCR1 and CCR5, which are receptors for the chemokines CCL5 (regulated on activation, normal T-cell expressed and secreted [RANTES]) and/or CCL3 (macrophage inflammatory protein [MIP]-1) produced at the airway level (82). Interestingly, freshly isolated human pulmonary DCs were found to specifically express both CCR1 and CCR5. Meanwhile, chemokines of the monocyte chemotactic protein (MCP) family appear to be important for the recruitment of DCs in a murine model of pulmonary Mycobacterium tuberculosis infection: mice genetically deficient for the corresponding chemokine receptor, CCR2, have a defect in the progressive accumulation of pulmonary DCs after inoculation with M. tuberculosis. This results in a secondary shortage in pulmonary T-cell recruitment, correlating with premature death, compared with wild-type animals (83, 84). In addition to chemokines, the airway epithelium could attract DCs by means of defensins. These are small cationic peptides with bactericidal activity, produced by epithelial cells after contact with pathogenic stimuli (85). Remarkably, human -defensin 2 (which is produced by airway epithelial cells [86]) was shown to engage CCR6, a chemokine receptor typically expressed by immature DCs homing to epithelia (87).

    Finally, nonmicrobial stimuli can also affect the steady-state recruitment of pulmonary DCs. Animals that are housed in specific pathogen-free, yet dusty conditions show an increased influx of DCs into the lung (58). Interestingly, ultrafine particulate matter triggers airway epithelial cells to produce the chemokine CCL20 (MIP-3), a major chemoattractant for CCR6-bearing immature DCs (88). In a model of allergic airway inflammation, CCR6 appears to mediate the recruitment of DCs into the inflamed lung, correlating with a burst of pulmonary CCL20 production a few hours after allergen challenge (89).

    It is not clear yet whether lung DCs are recruited from the blood in a differentiated form or as early precursors. Suda and coworkers (90) have shown that the pulmonary vasculature is enriched with direct DC precursors compared with the peripheral blood circulation. This pool of cells combines a close relationship to the lung tissue environment as well as the potential to differentiate rapidly in strongly immunogenic DCs. Also, the possibility of lung DC population renewal through local proliferation of intrapulmonary progenitors cannot be excluded. It is already known that steady-state pulmonary alveolar macrophage populations are predominantly maintained by in situ cell proliferation, and to a lesser extent by recruitment of monocytic precursors from the circulation (91). Moreover, in the skin, local cell division is the sole mechanism by which LCs appear to regenerate under noninflammatory conditions (92). It is important to note that granulocyte-monocyte colonyeCstimulating factor (GM-CSF), a key growth factor for "DC-poiesis," is expressed in significant amounts in the lung. GM-CSF production in the airways is increased in an inflammatory context (e.g., respiratory viral infection or exposure to environmental pollutants). Wang and colleagues (93) demonstrated how local transgenic overexpression of GM-CSF in the airways can result in a dramatic increase of pulmonary DC numbers. Another important hematopoietic growth factor for DCs is Fms-like tyrosine kinase 3 ligand (Flt-3L) (94). In contrast to GM-CSF, the potential source of Flt-3L within pulmonary tissues has not been mapped. Nevertheless, repeated injection of this cytokine greatly expands DC numbers in the lung parenchyma (95), and conversely, Flt-3LeCdeficient animals have a severe reduction in the number of lung interalveolar DCs, whereas airway mucosal DCs remain unaffected (96). These observations suggest that, similar to DCs in lymphoid organs, lung DCs do not constitute a homogenous population. Rather, lung DCs could fall into separate subsets with possibly different hematopoietic origins.

    In summary, DCs can populate the lung through different mechanisms (Figure 5). DCs present in the blood circulation could be directly recruited by means of appropriate pulmonary chemokine signals. Alternatively, monocytic DC precursors could first be chemoattracted from the blood into the lung and subsequently differentiate into DCs under the influence of cytokines secreted by resident pulmonary cells (e.g., GM-CSF produced by respiratory epithelium). In addition, a hypothetical mechanism for maintaining lung DC homeostasis might be proliferation of putative intrapulmonary DC progenitors, induced by growth factors secreted by resident pulmonary cells (GM-CSF or Flt-3L). Finally, indirect evidence points to the possibility of transdifferentation of pulmonary macrophages into DCs under the influence of GM-CSF (93).

    Lung DCs Continuously Report Antigenic Information from the Airways to Pulmonary LNs

    One of the most crucial specialized functions of DCs is the capture and delivery of antigen to local lymphoid tissues. These are the privileged sites for potential encounters between APCs and antigen-specific lymphocytes (i.e., the basis for mounting an adaptive immune response). The dense superficial network of airway mucosal DCs is ideally positioned for the interception of any potential antigen in the inhaled air. In addition, pulmonary DCs possess the necessary molecular equipment for efficient sensing and sampling of a wide variety of airborne antigens. Receptors of the C-type lectin family are an important family of molecules in this respect (97). These transmembrane sugar-binding proteins act as "pathogen recognition receptors," recognizing carbohydrate motifs present on the surface of several microbial organisms. In addition, they deliver captured antigens to endocytic vesicles for further processing and routing to the MHC class II presentation pathway. Several C-type lectins have been described on pulmonary DCs. Cochand and colleagues (56) revealed a high expression of mannose receptor on lung parenchymal DCs, endowing these cells with a robust endocytic capacity for mannosylated antigen. It is known that several important lung pathogens, such as M. tuberculosis, Pneumocystis carinii, as well as many fungi, display mannose sugars on their surface. DC-SIGN (DC-specific intercellular adhesion molecule [ICAM]-3eCgrabbing nonintegrin), a newly described C-type lectin, appears to be the principal molecule through which M. tuberculosis enters pulmonary DCs (98). DC-SIGN also has affinity for galactomannans present on the cell wall of Aspergillus fumigatus (99). Consequently, binding and internalization of A. fumigatus conidia by DCs correlate with DC-SIGN expression on the surface of these cells. Other lectin-type receptors that have been documented on subsets of lung DCs are Langerin (43, 51), BDCA-2 (51), and, at least in the mouse, DEC-205 (100). However, their function with respect to specific antigen recognition and endocytosis is currently poorly defined. Additional receptors with a role in antigen uptake have been detected on pulmonary DCs: these include IgG-Fc receptors, for the capture of antibodyeCantigen complexes, and C3bi-R (or Mac-1), which binds opsonizing complement fragments (4).

    Using a mouse model, we have shown that antigen uptake by airway DCs can proceed without any breach to the mucosal barrier, and in the absence of any inflammatory stimulus (101). This is surprising given that DCs of mouse intrapulmonary airways are predominantly located underneath the airway epithelial basement membrane, and that these experiments involved administration of large (i.e., nonpermeant) macromolecules in the airways using a rigorously nontraumatic and sterile instillation technique. This could point to an antigen capture mechanism as described in a recent study on the gut mucosa: indeed, despite their subepithelial location, DCs in the intestinal lamina propria are perfectly capable of capturing noninvasive antigens by extending interepithelial pseudopods toward the lumen without disrupting the epithelial barrier's integrity (102).

    The instillation of inert fluorescent macromolecules into the airways enabled us to track DCs migrating and transporting antigen from the airway mucosa toward pulmonary LNs (Figure 6) (101). This transport was rapid, occurred constitutively (i.e., in the absence of inflammation), and the migratory DCs were seen to specifically penetrate the T-cell zones of the mediastinal lymph nodes (MLNs). These observations confirm earlier studies suggesting that the steady-state recruitment of DCs into the lung is balanced by a continuous emigration of these cells to the MLNs (57). Also, intratracheal administration of soluble protein antigen results in the appearance of strong antigen-presenting activity in the draining MLNs, with similar kinetics (103). Analogous conclusions were reached using intratracheal transfer of in vitroeCderived DCs (104, 105), although these cultured DCs might not reflect the exact nature of the endogenous pulmonary DC populations in terms of phenotype, activation level, and antigen-uptake capacity.

    Much research has been devoted to the molecules that help DCs "navigate" toward the T-cell areas of local LNs. Insights into the mechanisms involved might lead to therapeutic strategies in which elicitation of inappropriate immune responses could be averted by blocking antigen transport to LNs. Alternatively, this knowledge could lead to improved vaccine design by optimizing DC homing to LNs. In general, activated DCs use the chemokine receptor CCR7 to guide themselves along chemokine gradients within afferent lymphatic vessels, all the way down to the LN's T-cell areas (106). The CCR7-triggering chemokines expressed in these structures are CCL21 (= SLC [secondary lymphoid organ chemokine]) and CCL19 (= MIP-3) (107, 108). Surprisingly little is known regarding the involvement of this molecular network in the trafficking of lung DCs. In one report, pulmonary CCL21 expression was detected in a peribronchial and perivascular pattern, with virtual absence in the alveolar zones (109). This pattern probably corresponds to the distribution of the deep pulmonary lymphatic vessel plexus and might delineate the migratory route of LN-homing lung DCs. Accordingly, in vivo neutralization of CCL21 could prevent DC homing to pulmonary LNs and the subsequent triggering of a T-celleCdriven immune response (110). In addition to chemokines, lipid metabolites such as leukotrienes and prostaglandins are emerging as important upstream controllers of DC migration toward LNs. It was shown that DCs require the presence of the Cys-leukotriene LTD4 in the immediate extracellular space to be responsive to chemoattraction by CCL19 (111). Prostaglandin E2 (PGE2) produced by epithelial cells after antigen exposure can also stimulate DC emigration toward draining LNs (112, 113). In contrast, PGD2 exerts an opposite effect (114): a recent study showed that PGD2 could inhibit the emigration of airway DCs toward MLNs and consequently prevent the induction of a primary immune response. The same effect was obtained with pharmacologic agonists of the peroxisome proliferator-activated receptor (PPAR-), an important intracellular mediator of prostaglandin signaling (115, 116).

    As mentioned in the INTRODUCTION, the presence of an inflammatory process at antigen-exposed surfaces is a strong stimulus for the migration of antigen-transporting DCs toward LNs. Transposed to the lung, this would result in an increased flow of antigenic information from the airways toward the MLNs. We have studied this phenomenon in a model of allergic airway disease, and found that ongoing airway inflammation causes a massive and accelerated flux of allergen-transporting DCs from the airway mucosa to the MLNs (117). This is probably due to the intense release of DC-activating inflammatory molecules, such as tumor necrosis factor (TNF-) and prostaglandins, during allergic airway inflammation. Whether this phenomenon contributes to the amplification of the allergen-driven immune response remains to be investigated.

    DCs Translate Signals from the Pulmonary Environment into a Specific Immune Response

    After arriving into the LNs, DCs face their last and most important task: that is, instruct T cells to respond to presented antigen in the most adequate way. The type and activation state of the DC, the dose of antigen, as well as the nature of concomitant environmental factors present at the time of antigen encounter determine the nature of the resulting T-cell response. Currently, three different possible outcomes for effector T cells are distinguished. A T-helper 1 (Th1) response is characterized by the production of IFN- and TNF by T cells. It is the normal outcome after DC exposure to viruses or bacteria and is crucial for the control of intracellular pathogens such as Mycobacterium spp. It is also the basis of the delayed type hypersensitivity reaction. Th2 differentiation usually occurs after contact with extracellular parasites (e.g., helminths) and involves production of cytokines such as interleukin 4 (IL-4), IL-5, IL-9, and IL-13, resulting in IgE production as well as accumulation of eosinophils and mast cells. Allergens are nonpathogenic environmental antigens that elicit an inappropriate Th2 response. A third main outcome is the induction of tolerogenic or regulatory T cells producing immunosuppressive cytokines, such as IL-10 or transforming growth factor (TGF-). This is probably the most prevalent response in steady-state conditions. It forms a constant safeguard against the emergence of inappropriate inflammatory reactions to harmless antigen. The way this paradigm can be transposed to the lung's immune homeostasis is summarized in Figure 7.

    It has long been proposed that the airway mucosa is inherently Th2-biased, providing a counterbalance to potentially tissue-damaging Th1 reactions to harmless inhaled antigen. A few studies were aimed at demonstrating the involvement of pulmonary DCs in this phenomenon. Lung DCs were found to produce cytokines such as IL-10 and IL-6, which have often been considered as Th2-skewing (although this remains controversial). In addition, pulmonary DCs showed an impaired ability to produce the Th1-inducing cytokine IL-12 (118, 119). However, a DC-promoted Th2 climate does not necessarily imply protection from inflammation. Lambrecht and colleagues (104) showed that antigen-loaded DCs transferred into the airways of healthy animals migrate to the MLNs and evoke a highly inflammatory Th2-type sensitization. This experiment left open the question concerning the role of the lung's own DCs in the control of the default pulmonary immune response. The latter is more and more regarded as strongly tolerogenic or regulatory by nature, thereby ensuring the protection of the delicate gas exchange structures from excessive inflammation, be it Th1- or Th2-driven. This raises two important questions: (1) Can the induction of tolerance or immunity to inhaled antigen be assigned to specific DC subtypes and (2) What are the molecular mechanisms involved in this process Recently, pDCs in the lung have been described as important actors in the maintenance of tolerance to inhaled antigen (120). This property was attributed to these cells transporting antigen to the thoracic LNs while maintaining low levels of T-cell costimulatory molecules, and high levels of the inhibitory molecule PD-L1. As a result, pulmonary pDCs failed to trigger antigen-specific T-cell proliferation and production of effector cytokines, but induced immunosuppressive T cells instead. Meanwhile, several studies support a concept of duality in pDC function: in baseline conditions, pDCs would exist in a quiescent state with weak immunostimulatory capacity and the ability to induce tolerance, whereas after appropriate stimuli (most notably viral exposure), pDCs would switch to an immunogenic state characterized by an impressive production of type I interferon (121). This paradigm sheds a new light on the recent observation that a totally inert and tolerogenic protein can become immunogenic when coinhaled with a respiratory virus (122).

    Nevertheless, induction of tolerance in the lung is unlikely to be the exclusive function of pDCs. Mice deficient for Flt-3L, a key growth factor for pDCs, show no impairment in the development of tolerance to harmless inhaled antigen. In addition, the mDCs that transport protein antigen to the MLNs produce IL-10 and express high amounts of inducible costimulator ligand (ICOS-L), both of which lead to the induction of antigen-specific regulatory T cells with the power to inhibit airway inflammation (123, 124).

    As expected, the presence of microbial organisms in the lung modifies the outcome of antigen presentation by DCs in the pulmonary LNs. As an example, a single pulmonary delivery of influenza virus leads to a transient amplified flux of DCs toward the MLNs, generating influenza-specific CD8+ T cells that produce large amounts of IFN- (125). Heat-killed Listeria monocytogenes (126) or Aspergillus fumigatus (127) delivered into the airways are also rapidly transported to the MLNs by DCs, leading to the priming of CD4+ T cells. Remarkably, the pulmonary DC is able to discriminate among different fungal components: phagocytosis and processing of Aspergillus conidia induces a Th1 response, whereas uptake of hyphae results in Th2 polarization.

    The immune response initiated by pulmonary DCs is not only preconditioned by stimuli from the inhaled air. The lung's own cells provide numerous molecular signals that are known to affect DC function in some way. Significant insight has been gained regarding the coexistence of pulmonary DCs and macrophages. In the lung parenchyma, macrophages in the alveolar lumen and DCs within interalveolar septa are separated by a fraction of a micrometer. It has repeatedly been reported that alveolar macrophages inhibit DC functions through the production of soluble mediators (128). Alveolar macrophageeCderived nitric oxide was shown to inhibit MHCII expression on lung DCs and suppress their T-cell stimulatory activity (129). Other DC-inhibiting factors secreted by alveolar macrophages include prostaglandins, H2O2, TGF- (130), and IL-10 (131), as well as decoy receptors for IL-1 and TNF (132). Together, these data suggest that pulmonary macrophages exert their well-known immunomodulatory function through an important restraining influence on DCs. In this view, noninvasive aeroantigens could be taken care of by scavenging macrophages crawling over the airway surface, and these cells would produce mediators that prevent the triggering of DC activation. However, damage to the macrophageeCsurfactanteCepithelium barrier would allow antigen to reach deeper sentinel DCs and would shift the local cytokine environment in favor of DC activation and the initiation of an adaptive immune response. Intriguingly, interstitial macrophages can exert a supportive influence on pulmonary DC immune function by preprocessing particulate antigen into smaller peptides that are then loaded on the surface of neighboring DCs (133, 134).

    In contrast to DCeCmacrophage dialogs, the interaction of pulmonary DCs with other prominent cells of the lung has been less studied so far. Nevertheless, airway and alveolar epithelial cells, fibroblasts, mast cells, nerve endings, and lymphocytes all express mediators that are generally known to affect the immunomodulatory function of DCs. The putative interactions of all these pulmonary cell types with DCs (summarized in Figure 8) are a vast and largely unexplored research terrain with important therapeutic implications.

    DCs IN HUMAN LUNG DISEASE: FRIEND OR FOE

    Given the DC's pivotal role in controlling pulmonary immunity, it follows that any aberration in DC function can have a considerable clinical impact. This section reviews the emerging knowledge on the role of DCs in several major lung pathologies.

    Allergic Asthma

    Asthma is a chronic inflammatory disorder of the airways featuring bronchial smooth muscle hyperreactivity, congestion of the airway mucosa, and excessive mucus secretion. This results in characteristic symptoms of wheezing, coughing, and dyspnea. These manifestations are typically variable and the airflow limitation is often reversible. Importantly, there is a relentless increase in asthma incidence throughout the world (www.ginasthma.org).

    The last decades have seen a growing insight in the cellular and molecular mechanisms underlying allergic asthma. Cutting-edge experimental research has progressively shifted the focus from downstream effectors, such as mast cells, IgE, and eosinophils, up to the Th2 lymphocytes and their proallergic cytokine products (e.g., IL-4, IL-5, IL-13) (135). More recent research by our group and others has implicated the DC as an even more upstream instigator in the allergic inflammatory cascade. Introduction of antigen-loaded DCs into the airways of healthy animals is sufficient to induce allergic sensitization to that antigen (104). Conversely, selective elimination of DCs during ongoing allergic airway inflammation results in the virtual disappearance of the inflammatory symptoms (54). Importantly, other APCs in the lung, such as macrophages or B cells, are unable to take over the fundamental role of DCs in the initiation or maintenance of the eosinophilic inflammation (136, 137).

    Experimental studies point to several properties of lung DCs that could account for their crucial role in the maintenance of Th2-based inflammation to inhaled antigen. First, DCs are recruited in massive amounts to the lung during allergic airway inflammation. At the plateau of eosinophilic inflammation, recovery of DCs from BALF is increased 30- to 100-fold (117, 138eC140). This increase is supported by a proliferation of early DC precursors in the bone marrow (140), suggesting possible bone marroweCstimulating signals emanating from the inflamed airways, as was already reported for eosinophils (141). Second, DCs within inflamed airways are unusually activated compared with DCs from healthy lungs: cell surface expression of MHCII and T-cell costimulatory molecules is markedly enhanced, whereas levels of ICOS-L, a molecule involved in the induction of inhalation tolerance (142), are decreased (117). In addition, DCs are the chief producers of the chemokine CCL17 in the lung (139). CCL17 ("TARC" [thymus- and activation-regulated chemokine] in the old nomenclature) is a molecule that specifically attracts Th2 lymphocytes toward APCs (143). The interaction of airway DCs with these allergen-specific T cells leads to reciprocal activation and precedes the appearance of the late-phase asthmatic response (144). Seen as a whole, the local DC activation within the airways, together with the immediate exposure to aeroallergen and the concomitant recruitment of airway T and B cells, could provide an adequate microenvironment for an in situ perpetuation of the chronic airway inflammation. In one report, it was even suggested that the chronicity of allergic airway disease could be attributed to the existence of an exceptionally long-lived subset of allergen-presenting DCs in the BALF (145).

    As would be expected from these data, molecular defects that impair the mobilization of DCs into the lung during allergen exposure should lead to diminished airway inflammation. We and others have identified matrix metalloproteinase 9 (MMP-9) as a critical molecule enabling the entry of DCs into the airways (139, 146). MMP-9 is an MMP that breaks down basement membranes and allows migratory cells to pass from one tissue compartment to another. MMP-9 deficiency impairs DC accumulation after allergen exposure, resulting in a local shortage of CCL17 and ultimately a collapse of the allergic airway inflammation. A summary of experimental insights concerning the role of DCs in the sensitization and maintenance of allergic airway inflammation is provided in Figure 9.

    The relative contribution of mDCs versus pDCs in the pathogenesis of allergic airway disease is a relatively recent subject of debate. Originally, pDCs were termed "DC2," based on a Th2-polarizing character. However, this Th2 effect was probably an artifact of specific in vitro culture conditions (147). It is now clear that, depending on the stimulus, pDCs can initiate Th1- and Th2-biased responses alike (148). It was recently shown that pulmonary pDCs possess some "antiallergic" properties: selective in vivo elimination of pDCs from healthy lungs unleashes severe allergic responses to otherwise tolerogenic inhaled antigen (120). There is additional evidence supporting a potential antiallergic effect of pDC function. It has been shown that administration of CpG oligonucleotides can provide protection from allergic airway inflammation, in a way that is mostly independent of Th1 cytokine production (149). CpG oligodeoxynucleotides are typically known as powerful activators of pDCs, because these cells express the corresponding TLR (TLR9). In vitro studies show that CpG-stimulated pDCs can inhibit Th2 cell proliferation via IFN-/ production (150). These experimental data also suggest that immunomodulatory molecules emerging as antiasthmatic therapies primarily achieve their effect by targeting lung DCs.

    Research on human subjects has provided some important insights on the function of DCs in asthma as well. In patients with asthma, allergen challenge causes a sharp decline in the number of circulating blood mDCs within a few hours (151). During the same timeframe, a rapid accumulation of mDCs occurs within the bronchial mucosa (152). This suggests that, in subjects with asthma, an alteration occurs in the lung's chemokine networks, allowing a rapid entry of blood-borne mDCs into the allergen-exposed lung (pDCs do not seem to be affected in the same way in these studies). Recently, the acute drop in circulating mDCs after allergen challenge was shown to be inhibited by treatment with the cysteinyl leukotriene 1 (CysLT1) receptor antagonist pranlukast (153). This was associated with a decreased production of the DC-attracting chemokine CCL20 (measured in induced sputum), and consistent with the expression of the CysLT1 receptor on circulating mDCs. Earlier studies using bronchial biopsies had already documented an increase in the number of intraepithelial airway DCs in subjects with asthma compared with healthy individuals, and this number returned to control levels after inhaled corticosteroid treatment (it is known from animal studies that glucocorticosteroids induce apoptotic depletion of the airway DC network [53]) (154). A functional comparison between bronchial epithelial DCs isolated from healthy atopic versus atopic donors with asthma yielded interesting results: the respiratory epithelium of subjects with asthma was strongly enriched with CD1a+ DCs, and these cells preferentially induced the production of IL-4 and IL-5 from sensitized autologous Th cells (50). Also, CD1a+ airway mucosal DCs from patients with asthma displayed increased surface levels of FcRI, the high-affinity receptor for IgE, which could help DCs collect IgE-coated allergen on their surface (155).

    Additional studies using human blood as a starting material further confirm that DCs from patients with asthma or allergy are "altered" in a way that secures a perpetuation of the inappropriate Th2 response. The possible role of environmental agents in this phenomenon is the subject of intense research. Diesel exhaust particles have often been proposed as Th2-inducing "adjuvants," and it was recently shown that these pollutants can establish a Th2 milieu by influencing both the DC as well as the responder T cell (156). In addition, diesel exhaust particles cause inflammation at the level of the airways by means of reactive oxygen species (157). This would result in DC activation and thus amplify DC-mediated antigen transport toward MLNs, where antigen would be presented in the context of the Th2-biasing signals. More recently, pollen-derived isoprostanes were shown to activate DCs and turn them into Th2 inducers (158). Additional indoor sources of proallergic factors have also been identifed, such as house dust mites thriving in overinsulated houses or cockroach allergens in inner city areas. Der p-1, a protein found in fecal pellets of the house dust mite Dermatophagoides pteronyssinus, has interesting properties with respect to DC biology. This molecule exhibits proteolytic activity and was shown to cleave epithelial tight junction proteins (159), thereby facilitating the delivery of antigen to intra- or subepithelial DCs. Meanwhile, the disturbance in the epithelial integrity would constitute a danger signal and lead to DC activation. Also, bronchial epithelial cells produce several DC-attracting chemokines after exposure to Der p-1 (160). In several studies, human bloodeCderived DCs were exposed to house dust miteeCderived proteins in vitro. From these investigations, it appears that only DCs obtained from atopic subjects exhibit a proallergic function on exposure to house dust mite protein, whereas DCs from healthy subjects induce no T-cell polarization or even maintain tolerogenic properties (110, 161, 162). Intriguingly, only DCs from atopic individuals secrete high levels of the Th2-attracting chemokines CCL17 and CCL22 after Der p-1 exposure (163). The reason why DCs from atopic individuals are "hard-wired" to preferentially induce and attract proallergic T cells is still obscure. To date there is virtually no evidence for genetic polymorphisms determining the T-celleCpolarizing function of DCs in atopy. Much more research is addressing the question of how environmental influences can help establish an inappropriately Th2-oriented immune climate, sometimes for life. Further exploration of this issue from a DC standpoint might provide a mechanistic basis to the so-called hygiene hypothesis for the increasing prevalence of allergy. This theory proposes that the immune system of infants needs Th1-inducing stimuli (typically provided by microbial exposure) to evolve from an immature, Th2-biased immune response. The more "aseptic" Westernized urban lifestyle, where use of antibiotics and vaccines is widespread and orofecal pathogen burden is low, implies a shortage of such Th1-promoting triggers, thus creating an allergy-prone situation. Alternatively, inappropriate Th2 responses might arise from a failure of tolerogenic mechanisms, rather than from a lack of Th1 stimuli: Wills-Karp and coworkers (164) recently proposed a refinement to the hygiene hypothesis, in which a continuous low level of microbial stimulation (presumably from gut commensals) would ensure a tolerogenic climate dominated by the production of the immunosuppressive cytokine IL-10. Absence of such "counterregulatory" stimulus would thus remove an important inhibition on inappropriate Th2 (allergic) or even Th1 (autoimmune) immune responses.

    There are some interesting elements pointing to the immediate relevance of DCs to the hygiene hypothesis, although many aspects of this complex relationship still need to be resolved. The "immature" character of mucosal immunity in early life might be attributed to the state of the DC system during that period: compared with the adult situation, DCs within neonatal airways are not only less numerous and less mature in terms of MHC expression (58) but also hyporesponsive to inflammatory stimuli (165). In addition, DCs from neonates show an impaired production of IL-12, leading to a defective capacity to induce Th1 responses (166). Holt (167) suggested that a delay in the postnatal acquisition of Th1 competence could explain the difference between atopic and nonatopic individuals. However, in line with the ideas put forth by Wills-Karp and colleagues, we argue that chronic low-level exposure to microbial stimuli would help mucosal DCs evolve toward a tolerogenic rather than a Th1-inducing function in the first place. From that point on, tolerogenic DC networks at mucosal surfaces would constitute the prime sensors for any additional Th1- or Th2-inducing environmental signals, acting alone or in combination. As an experimental illustration of this concept, Eisenbarth and coworkers (168) showed how inert protein antigen coinhaled with low levels of LPS endotoxin triggers airway DCs to induce a Th2 rather than a tolerogenic antigen-specific response. In contrast, coinhalation of high doses of LPS led to a shift from a Th2- to a Th1-biased reaction (168). The modulation of DC-induced airway allergic responses by endotoxin was also confirmed in a report by Kuipers and colleagues (169). These experimental findings are in line with epidemiologic data in which exposure to house dust endotoxin was found to decrease allergic sensitization in infants at high risk of developing asthma (170). In another study, instillation of Dermatophagoides farinae proteineCexposed DCs into the airways of healthy mice led to allergic sensitization to that antigen. However, prior coexposure of the DCs to D. farinae extract together with respiratory syncytial virus shifted the pulmonary immune response in vivo from Th2 toward Th1 (171). It should be noted that this experiment involved exposure of mature DCs to respiratory syncytial virus. Primo-infection with respiratory syncytial virus during early infancy, a time when airway DCs are defective in Th1 polarization, is known to establish a Th2-biased climate in the airways, increasing the risk for the development of asthma in later life.

    Next to environmental stimuli, a number of studies have stressed the importance of tissue-derived factors in the conditioning of DCs toward a proallergic function. PGE2, which can be produced by airway epithelial cells, suppresses IL-12 production by DCs, leading to the development of IL-4eC and IL-5eCproducing T cells (172). Histamine, the prototypic mediator released by mast cells, triggers human DCs to induce Th2 immune responses as well (173), thus creating the possibility of a positive feedback loop involving IgE and activated mast cells (174). This finding sheds new light on the results of a large prospective study, in which intake of an antihistamine during infancy significantly decreased the risk of developing asthma in a subset of allergen-sensitized children (ETAC [Early Treatment of the Atopic Child] study [175]).

    GM-CSF, another product of the airway epithelium, is not only a DC differentiation factor but also a strong Th2-polarizing cytokine in vivo (176). This might explain why in vitroeCgenerated DCs (using an abundance of GM-CSF in the culture medium) induce allergic sensitization after intratracheal transfer, whereas endogenous airway DCs are tolerogenic by default. Thymic stromal lymphopoietin (TSLP), an IL-7eCrelated cytokine produced by epithelial cells and mast cells, is one of the most powerful triggers to date for DC-dependent allergic immune responses in humans (177). TSLP-exposed DCs secrete high amounts of the Th2-attracting chemokines CCL17 (TARC) and prime naive Th cells to produce proallergic cytokines (IL-4, IL-5, IL-13). Although TSLP is expressed in the normal lung and overexpressed in the skin of patients with atopic dermatitis, TSLP levels in asthmatic lungs have not been investigated yet, something that could have important therapeutic implications. Equally important is knowing which environmental factors might trigger an overproduction of TLSP by pulmonary cells.

    In summary, there is compelling evidence to conclude that DCs play a pivotal role in the pathogenesis of allergic asthma. Experimental data indicate that DCs are obligatory APCs for the initiation and maintenance of allergic airway inflammation. In humans, the presence of asthma is associated with an increase in DC numbers in the bronchial mucosa. This increase can be caused by a strikingly rapid movement of circulating DCs into the lung tissue after allergen exposure. Meanwhile, DCs from allergic individuals seem to lose their tolerogenic character and instead perpetuate the allergic state through the expression of costimulatory molecules, cytokines, and chemokines that favor Th2 responses.

    Chronic Obstructive Pulmonary Disease

    In contrast to allergic asthma, the role of DCs in chronic obstructive pulmonary disease (COPD) has been much less investigated. COPD encompasses two clinical entities, each of which correlates with specific histopathologic features. On one hand, there is chronic obstructive bronchiolitis characterized by inflammatory infiltrates surrounding peripheral airways, leading to poorly reversible airflow obstruction (www.goldcopd.com). On the other hand, there is emphysema, which involves a destruction of interalveolar septa with a progressive decrease of the gas exchange surface. The inflammatory infiltrate in COPD contains mainly neutrophils, CD8+ (cytotoxic) T cells, and monocytes/macrophages (reviewed in Reference 178), a combination of cells that has not been fitted into a clear pathogenetic mechanism yet (in contrast to the Th2 lymphocyte/eosinophil presence in asthma).

    Recently, we documented a relentless increase in lung DCs in a murine model of tobacco smokeeCinduced pulmonary emphysema. After 6 months of smoke inhalation, DC numbers in the BALF were 10-fold greater than those observed in control animals (25). An earlier study by Zeid and Muller (179) documented a similar increase in pulmonary Langerhans-like cells on tissue sections of tobacco smokeeCexposed mice. In contrast to these studies, Robbins and coworkers (180) reported a decrease in pulmonary DC numbers after smoke inhalation. The reason for these divergent observations can be attributed in part to the methodology used for the detection of DCs and also to large differences in the smoke exposure regimen (a relatively low dose was used in the latter study).

    In humans, increased numbers of CD1a+ DCs were detected in the airway mucosa of patients with COPD and these numbers declined after fluticasone proprionate inhalation (181). It should be noted that smoking by itself induces an increase in DC numbers in the airways, regardless of the presence of COPD (182, 183). The association of COPD with smoking suggests an innate inflammatory response to inhaled toxic components. It is very likely that the airway DC network is acutely sensitive to smoke inhalation: tobacco smoke contains many potential DC-activating components such as reactive oxygen species and endotoxin. With respect to the latter, we have recently observed a TLR4-dependent activation of pulmonary DCs after smoke inhalation (TLR4 is the signaling receptor for LPS; Maes and colleagues, unpublished manuscript, and Reference 26). In addition, tobacco smoke could trigger airway epithelial cells to release DC-activating factors, such as TNF-, GM-CSF, or heat-shock proteins. It is tempting to speculate that the smoke-activated DCs would lose their default tolerogenic character and induce a sustained immune response to otherwise harmless antigens present in the tobacco smoke (e.g., tobacco glycoprotein). Alternatively, intracellular components released through toxic damage could be chemically altered by smoke and become immunogenic. DCs would then take up, process, and present these modified intracellular antigens to CD8+ cytotoxic T cells. The dangerous combination of activated DCs and an abundance of these "new" antigens could set the stage for a self-perpetuating, tissue-directed immune response with devastating consequences in the long term. This acquired immune response could form the basis for the relentless progression of inflammation observed in patients with severe COPD even after smoking cessation. This disturbing phenomenon was revealed in a study by Retamales and coworkers (184), but was rather attributed to latent adenoviral infection of lung epithelial cells, the degree of which was correlated with emphysema severity and associated with persistent inflammatory cell recruitment despite cessation of smoking. Chronic viral infection could indeed provide a plausible explanation for the relative increase in CD8+ T cells in the airway infiltrates of patients with COPD. Interestingly, smokers with airway obstruction have elevated levels of a specific latent adenoviral DNA sequence compared with smokers without obstructive disease (185). In addition, CD8+ T cells were shown to mediate cytotoxic damage to airway epithelial cells when these were expressing a viral antigen (186). Here again, DCs are known to be required for the initial sensitization of T cells to the viral antigens, either through direct infection of the DCs themselves or after uptake and processing of fragments from infected epithelium (187).

    There are some tantalizing hints suggesting a possible role of DCs in the development of emphysema itself. An indirect indication is that LC histiocytosis (LCH) of the lung, which is also associated with smoking and involves a pathologic accumulation of LCs, is accompanied by destructive lesions in the alveolar zones. On a cellular and molecular level, it has been shown that, during the differentiation from monocytes, DCs show an impressive upregulation of transcripts for human macrophage elastase or MMP-12 (188). MMP-12 appears to be crucial for the induction of emphysematous changes in an animal model of tobacco smoke inhalation (189). In addition, transgenic animals with inducible TNF- have an increase in pulmonary MMP-12 levels and spontaneously develop emphysema (190). TNF- is increased in the sputum of patients with COPD (191) and is a strong activator of DC maturation and trafficking (192, 193). Recently, BALF macrophages from patients with COPD were found to display an increased elastolytic activity in vitro, together with increased expression of MMP-12 mRNA. However, as often in similar studies, BALF cell differentiation is performed on a simple morphologic basis, which precludes any accurate distinction between macrophages and DCs. An interesting observation is that elastin fragments generated through the proteolytic activity of MMP-12 are strongly chemotactic for monocytes (194). An interesting hypothesis would be that the continuous inflammatory transit of DCs through elastin-rich alveolar regions maintains or even amplifies itself by means of chemotactic degradation products. As an indication for such a phenomenon, DC migration into inflamed lung interstitium and BAL compartment is decreased in MMP-12eCdeficient mice (our unpublished observations).

    Further studies in animal models will be necessary to determine whether the pathogenesis of COPD relies in substantial amount on a pathologic response of DCs to tobacco smoke components. These investigations might lead to the discovery of several subentities within COPD, each based on the relative contribution of innate versus adaptive pathologic immune responses in the lung. It is hoped that these insights will help to extend the field of research toward novel targets in COPD treatment.

    Pulmonary LCH

    LCH is a disease characterized by an abnormal accumulation of Langerhans-like cells in one or several organs. Nowadays, the term LCH is used to encompass several clinical entities distinguished on the basis of organ involvement (solitary bone lesions in eosinophilic granuloma, as opposed to systemic involvement in Hand-Sche筶ler-Christian disease, Letterer-Siwe disease, and histiocytosis X). The link between histiocytosis X and Langerhans cells was suggested decades ago by the finding of Birbeck granules in the "histiocytes" accumulating in these lesions (195). The first detailed account of pulmonary involvement was published by Auld (196) in 1957. Classical LC markers, such as CD1a, S-100, and Langerin, are used for the immunohistologic diagnosis of LCH (Figure 10). Langerin has even been suggested as a diagnostic tool for the detection of LCs in the BAL of patients with pulmonary LCH (197). In addition to LCs, LCH granulomas contain macrophages, lymphocytes, and eosinophils (hence the occasional name of "eosinophilic granuloma").

    The disease initially involves granulomatous infiltrations around distal airways. Progression into alveolar zones leads to cystic lesions surrounded by a fibrous reaction. In contrast to the systemic forms of LCH, which typically develop in children, pulmonary LCH is mainly seen in adults and shows a clear association with smoking. Although pulmonary LCH is a rare disease (precise data on prevalence are currently unavailable), a dissection of the pathogenetic mechanisms involved could lead to useful insights on the homeostasis of DCs in the lung in general. There is still much speculation concerning initiating triggers. Tobacco smoke in itself induces an increase in LC numbers in the airway epithelium (182). However, the transition to unbridled accumulation of LCs likely requires additional factors, which could be genetic predisposition, acquired mutations (allelic loss at the level of tumor suppressor genes has been described in LCH lesions [198]), or maybe another environmental trigger, such as viral infection. The accumulation of LCH cells could be due to a local proliferation of putative LC precursors (199, 200), a proliferation that could even be clonal in nature (201). Nevertheless, LCH lacks true features of neoplasia because proliferation rate is very slow (202), lesions are often spontaneously remissive, and LCs are virtually absent from end-stage fibrocystic lesions. Alternatively, LCH lesions could grow through continuous recruitment of new cells. Indeed, the LCs of LCH were shown to express CCR6 as well as its ligand CCL20 (MIP-3) (203): this could imply a paracrine and autocrine mechanism for a self-perpetuating attraction and retention of LCs into the granuloma.

    There is still debate concerning the activation/maturation status of LCs in LCH lesions. In one study, LCH cells were described as having low levels of CD83 and B7-2, and weak T-cell stimulatory capacity (204). Combined with overexpression of CCR6, these findings suggest an immature phenotype, except in self-healing LCH lesions where the LCs appeared mature (204). The immature character of LCH cells seemed to correlate with the presence of numerous IL-10eCsecreting cells in the direct tissue environment. However, these observations were made in bone and skin LCH lesions; similar investigations performed in the lung show that LCs in pulmonary LCH are clearly mature, with very high expression of B7-1 and B7-2 (205). The mature/activated state of pulmonary LCH cells was clearly supported by the local presence of a DC-activating cytokine milieu with elevated IL-1 and low levels of IL-10. A robust increase in GM-CSF production has been documented in LCH lesions (206), whereas increased TNF- has been described in extrapulmonary LCH (207). Notably, both cytokines are known to be critical for the hematopoietic development of LCs (208). A recent study reported elevated levels of Flt-3L and stem cell factor (SCF) in the serum of patients with LCH (209), a combination of hematopoietic growth factors that was shown to sustain long-term expansion of primitive DC precursors (210). In addition, the abundant production of TGF- around LCH lesions (211), combined with GM-CSF, might allow freshly recruited monocytes to differentiate locally into LCs and thus contribute to lesion growth (212).

    It is still unclear why granulomatous LCH lesions at the level of the bronchioles evolve into fibrocystic scars in the alveolar zones. Additional studies on MMP production by LCH cells might shed some light on the process and possibly provide a link with the development of emphysema in smokers. Hayashi and colleagues (213) described overexpression of the collagenolytic MMP-2 in pulmonary LCH cells. Also, the cytokines that are overexpressed in LCH lesions are known to be strong inducers of MMPs in cells of monocytic/dendritic/macrophage lineage (214, 215). The role of non-LCs in LCH lesions is also worth examining. In particular, the interaction between LCH cells and T lymphocytes could be an important factor in the maintenance of the disease. Tazi and coworkers (205) reported a recruitment of CD40L-positive (i.e., activated) T cells around CD40-positive LCH cells, whereas T cells in uninvolved lung tissue were uniformly CD40L-negative. This finding, which was confirmed in pediatric cases of LCH (216), strongly suggest stimulatory, bidirectional interactions between LCH cells and T cells, possibly involving presentation of an as yet unidentified antigen. Tobacco glycoprotein might be a suitable candidate for driving the immune response in smokers with LCH. However, it was shown that lymphocytes from patients with LCH are hyporesponsive when stimulated with tobacco glycoprotein (217). In addition, engagement of CD40 on DCs or LCs leads to activation and cytokine production, even in the absence of cognate interactions (218). Hence, the presence of environmental or perhaps tissue-derived antigens may not be an absolute requirement for maintaining reciprocal LCeCT-cell activations in LCH granulomas. Another aspect of LCH is the frequent recruitment of eosinophils, suggesting some Th2-promoting mechanism. It would be interesting to examine whether TSLP, as a strong DC activator and inducer of Th2 responses, might be involved in the disease. It was recently shown that TSLP synergizes with CD40 engagement on DCs, leading to the induction of IL-5eC and IL-13eCsecreting cytotoxic T cells (219).

    As a whole, LCH remains a complex mix between reactive and neoplastic pathology. Nonetheless, ongoing investigations should continue to borrow knowledge gained in the field of experimental LC biology, in a process that will likely lead to promising therapeutic options for this puzzling disease.

    Lung Cancer

    Cancerous lesions elaborate an arsenal of tricks to evade immune defense: as such, they are perhaps the biggest challenge for the DC system. An insight in the way pulmonary malignancies affect the normal biology of DCs can help determine how best to improve the efficacy of cancer immunotherapy (however, it is by no means the purpose of this article to discuss the proliferation of DC-based cancer vaccines that are currently being developed or even clinically tested). Recent studies show that vascular-endothelial growth factor (VEGF), an important molecule for tumor-induced angiogenesis, is a suppressor of DC development and maturation (220, 221). In histologic analysis of noneCsmall cell lung cancer specimens, VEGF expression and the degree of DC infiltration are inversely related and of prognostic value, with the better prognosis in low-VEGF tumors with abundant DC infiltration (222). In contrast, GM-CSF expression in primary lung carcinoma (noneCsmall cell lung cancer and adenocarcinoma) correlates with increased infiltration of DCs and LCs (223, 224), but the prognostic significance of this finding has not been established. Overexpression of cyclooxygenase 2 (COX-2) by noneCsmall cell lung cancer has been documented as an indicator of poor prognosis (225). In addition, COX-2 and VEGF are both positively correlated in noneCsmall cell lung cancer specimens (226). Interestingly, animal experiments have shown that a whole range of DC functions, including antigen processing, expression of costimulatory molecules, and secretion of IL-12, are suppressed by tumor supernatant in a COX-2eCdependent fashion (227). PGE2, a major product of COX-2, inhibits development of DCs from bone marrow precursors, whereas EP2R knockout animals have longer survival times when inoculated with a lung carcinoma cell line (228). Neuropeptides secreted by small cell lung carcinomas, such as bombesin-like peptides, also interfere with normal DC function through inhibition of maturation and IL-12 production (229).

    An intriguing observation is the preferential infiltration of pDCs, rather than mDCs in noneCsmall cell lung cancer tissue specimens as well as draining lymph nodes (230). This is a finding of potential importance, because CD8+ T cells primed by mDCs display strong cytotoxicity and secrete large amounts of IFN- (232), both important assets for an efficient antitumor response (231). In contrast, CD8+ T cells primed by pDCs become tolerogenic T cells with poor cytolytic responses and elevated secretion of the immunosuppressive IL-10 (232). In addition, human pDCs express indoleamine 2,3-deoxygenase (IDO), an enzyme generating tryptophan catabolites, which are powerful suppressors of T-cell responses. Interestingly, experimental studies described IDO-positive pDCs in tumor-draining LNs, and these cells actively suppressed T-celleCdependent responses to tumor antigens (233). Finally, malignant tissues could disrupt the normal sentinel function of DCs by elaborating aberrant chemokine networks. In fact, several experimental cancer vaccination schemes already aim to improve intratumoral DC infiltration through local induction of DC-attracting chemokines (234, 235).

    Additional molecular mechanisms of lung tumoreCmediated DC suppression will surely be discovered in the future. It is hoped that this knowledge will help to refine DC-based vaccines that can finally "outsmart" the malignant cells and thus have a drastic impact on the poor prognosis of patients with lung cancer.

    Lung Transplant Rejection

    Lung transplantation is a vital therapeutic option in several end-stage lung diseases, such as cystic fibrosis, severe emphysema, idiopathic pulmonary fibrosis, or primary pulmonary hypertension. Unfortunately, compared with other vascularized allografts, lung transplants are prone to a higher incidence of life-threatening chronic rejection, which manifests itself clinically as bronchiolitis obliterans syndrome (affecting more than 10% of post-transplantation survivors per year [236]). Chronic rejection of allografts relies on a T-celleCmediated immune response against donor organ antigens. Increasingly, attention has been drawn to DCs as potential initiators of this reaction. There is a logical place for DCs in the so-called two-way paradigm of donor/acceptor immunologic interactions (237). On one hand, so-called central sensitization to the allograft is initiated in the lymphoid organs of the acceptor. This requires donor APCs emigrating from the donor organ into draining lymphoid tissues of the host. Donor-derived DCs, activated by profuse danger signals originating from the surgical trauma, should be good candidates for this task, provided that severed lymphatic connections have had enough time to reestablish themselves (238). The alternative mechanism for the initiation of rejection involves infiltration of the donor organ by host-derived APCs, a process known as "peripheral" sensitization. In this case, APCs and lymphocytes from the recipient would access the graft via the bronchial circulation and initiate a local T-celleCdriven immune response to donor antigens.

    A few clinical studies have examined the place of DCs in lung transplant rejection, by quantifying the infiltration of these cells in biopsies taken from allografts. Early reports have delivered conflicting results: depending on the methods used, there was either an increase or a decrease in DC numbers reported in the bronchial mucosa of lungs with post-transplantation bronchiolitis obliterans (239, 240). A recent study using more consistent markers (HLA-DR) and superior sampling techniques (endobronchial biopsy) reinforces the notion that DC infiltration is intensified in lung allografts, with chronic rejection as compared with stable transplants (241). Similar findings were made in a rat model, whereby host-derived DCs were seen accumulating in dense peribronchial aggregates for months after transplantation (242). These findings would favor the peripheral mode of allograft sensitization as the predominant process in cell-mediated lung transplant rejection. It should be noted, however, that trafficking of professional APCs to and from allografts is not necessarily detrimental to transplant acceptance. In several types of organ transplantation, including the lung, the establishment of microchimerism (i.e., the seeding of donor-derived leukocytes into acceptor lymphoid and nonlymphoid organs) is correlated with increased graft survival (243, 244). This paradox probably reflects the duality in DC function regarding induction of tolerance versus triggering of an active immune response. It has been proposed that the relatively better outcome of liver as opposed to lung transplants could rely on the hepatic cytokine environment strongly favoring the induction of tolerogenic DCs (245).

    There are several mechanisms through which DCs could induce tolerance. DCs expressing the proapoptotic receptor Fas-L are capable of deleting Fas-expressing T cells in vitro (246). Inspired by these findings, Min and coworkers (247) showed the induction of hyporesponsiveness to a vascularized allograft after injection of donor-derived, FasL-transfected DCs. However, this strategy should be used with great caution. Buonocore and coworkers (248) demonstrated that "FasL-DCs" can exacerbate allogeneic T-cell responses, and even provoke severe pulmonary granulomatous vasculitis after a single systemic injection (249). The reason for these discrepant results is obscure but might be related to differences in the degree of MHC mismatching. An alternative mode of tolerance induction is the generation of hyporeactive or "anergic" T cells by DCs displaying suboptimal levels of costimulatory molecules. Blockade of costimulatory pathways (e.g., using CD40L-blocking antibodies or CTLA-Ig fusion proteins) appears to be a viable strategy in rodent as well as primate transplantation models (250eC252). DCs can also suppress allogeneic T-cell proliferation by means of IDO (see LUNG CANCER). IDO-positive APCs appear to be present within the lung interstitium. Interestingly, overexpression of IDO in lung transplants is capable of abrogating graft rejection in an animal experiment (253). Finally, DCs appear to be involved in the generation of actively immunosuppressive or "regulatory" T cells. Currently, two main categories of regulatory T cells are distinguished (reviewed in Reference 254). On one hand, the inducible "Tr1" and "Th3" cells are immunosuppressive T cells that differentiate under the aegis of nonactivated DCs in the steady state. Tr1 and Th3 cells mediate immunosuppression through the secretion of IL-10 and TGF-, respectively. In turn, these cytokines suppress DC activation, thereby consolidating the tolerogenic climate. It remains to be investigated whether a relationship exists between DC-induced Tr1 or Th3 cell function and lung allograft survival. IL-10 has been shown to efficiently suppress T-cell proliferation and the production of inflammatory cytokines in alloreactions induced by human lung DCs (255). Interestingly, gene transfer of IL-10 is capable of preventing the development of airway fibroobliterating disease in an animal model of tracheal transplantation (256). The other class of immunosuppressive T cells is represented by the CD4+CD25+ "Tregs." These cells, which originate naturally from the thymus, maintain tolerance to self-antigen and also suppress allogeneic immune responses by cell contacteCdependent mechanisms (254). In addition, evidence exists that CD4+CD25+ Tregs need to collaborate with the DC-dependent Tr1 and Th3 cells to achieve optimal immunosuppression in vivo. Interestingly, a recent report showed a negative correlation between CD4+CD25+ cell counts in peripheral blood and the incidence of bronchiolits obliterans more than 3 years after lung transplantation (257). The Treg's high expression of CD25, which is the IL-2R subunit, warrants some caution with respect to using IL-2ReCblocking antibodies as immunosuppressive agents in transplantation medicine (depletion of CD25+ T cells in animals induces fulminant multiorgan autoimmune disease [258]) (259).

    Considering the experimental and clinical data available so far, it appears that DCs could be the key for controlling lung transplant rejection. A thorough knowledge of the anatomy and timing of DC-mediated allograft sensitization is necessary. Subsequently, more refined pharmaceutical interventions could be aimed at preventing activation of DCs in the graft as well as in the recipient, and/or actively support the function of tolerogenic molecules expressed on DCs.

    CONCLUSIONS AND PERSPECTIVES

    Insight into DC biology continues to expand at a furious pace, making it ever harder to define the "state of the art." The road from bench to bedside is particularly challenging when it comes to DC research. Luckily, scientists can nowadays draw from an ever-growing toolbox of techniques, such as gene transfections, RNA silencing, and so forth. However, as in other fields, the challenge will be to promote these cellular manipulations to clinically acceptable strategies. Because of the DC's powerful impact on the outcome of immune responses, any attempt to manipulate these cells for therapeutic purposes must walk the thin line between excessive immune suppression and sparking off autoimmunity. In addition, more fundamental research is needed before reaching the stage of clinical application. As a start, there is still a lot to be investigated in terms of cataloging different DC populations in the lung and documenting their respective function, origin, and relationship to other pulmonary cells. It can be expected that the continuing emergence of new DC markers will create a complex taxonomy that becomes as dendritic as the cells themselves. The next step will be to define with precision which molecular pathways are corrupted as DCs "switch" the normal pulmonary immune response to a pathologic one. Equally important is knowing which external factors divert the normal functions of pulmonary DCs and how genetic polymorphisms modulate the DC's susceptibility. As daunting as these tasks may seem, the reward in the field of pulmonary medicine will more than compensate for the efforts: DCs may hold the key to decisive breakthroughs in fighting asthma, COPD, and lung cancer, undoubtedly some of the world's major health issues in the present and in the foreseeable future.

    Acknowledgments

    The authors thank Prof. Dr. G. Joos, Prof. Dr. G. Brusselle, and Dr. I. Demedts for their critical reading of this manuscript. They also thank Dr. I. Demedts and Dr. S. Saeland for providing the micrographs of Langerin-stained pulmonary histiocytosis specimens and normal human bronchial tissue, respectively. In addition, the authors thank Greet Barbier, Eliane Castrique, Indra De Borle, Philippe De Gryze, Kathleen De Saedeleer, Marie-Rose Mouton, Ann Neessen, and Christelle Snauwaert for their technical contribution to this article.

    This article is dedicated to the memory of Prof. Dr. Romain Pauwels, who passed away January 3, 2005.

    REFERENCES

    Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice: I. Morphology, quantitation, tissue distribution. J Exp Med 1973;137:1142eC1162.

    Van Voorhis WC, Hair LS, Steinman RM, Kaplan G. Human dendritic cells: enrichment and characterization from peripheral blood. J Exp Med 1982;155:1172eC1187.

    Egner W, McKenzie JL, Smith SM, Beard ME, Hart DN. Identification of potent mixed leukocyte reaction-stimulatory cells in human bone marrow: putative differentiation stage of human blood dendritic cells. J Immunol 1993;150:3043eC3053.

    Sertl K, Takemura T, Tschachler E, Ferrans VJ, Kaliner MA, Shevach EM. Dendritic cells with antigen-presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura. J Exp Med 1986;163:436eC451.

    Pavli P, Maxwell L, Van de Pol E, Doe F. Distribution of human colonic dendritic cells and macrophages. Clin Exp Immunol 1996;104:124eC132.

    Prickett TC, McKenzie JL, Hart DN. Characterization of interstitial dendritic cells in human liver. Transplantation 1988;46:754eC761.

    Hart DN, Fabre JW. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med 1981;154:347eC361.

    Hart DN, Fuggle SV, Williams KA, Fabre JW, Ting A, Morris PJ. Localization of HLA-ABC and DR antigens in human kidney. Transplantation 1981;31:428eC433.

    Hart DN, Fabre JW. Major histocompatibility complex antigens in rat kidney, ureter, and bladder: localization with monoclonal antibodies and demonstration of Ia-positive dendritic cells. Transplantation 1981;31:318eC325.

    Steinman RM, Lustig DS, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice: 3. Functional properties in vivo. J Exp Med 1974;139:1431eC1445.

    Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice: II. Functional properties in vitro. J Exp Med 1974;139:380eC397.

    Steinman RM, Adams JC, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice: IV. Identification and distribution in mouse spleen. J Exp Med 1975;141:804eC820.

    Steinman RM, Kaplan G, Witmer MD, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice: V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro. J Exp Med 1979;149:1eC16.

    Masten BJ, Lipscomb MF. Comparison of lung dendritic cells and B cells in stimulating naive antigen-specific T cells. J Immunol 1999;162:1310eC1317.

    Nussenzweig MC, Steinman RM, Gutchinov B, Cohn ZA. Dendritic cells are accessory cells for the development of anti-trinitrophenyl cytotoxic T lymphocytes. J Exp Med 1980;152:1070eC1084.

    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767eC811.

    Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001;13:114eC119.

    Huang FP, Platt N, Wykes M, Major JR, Powell TJ, Jenkins CD, MacPherson GG. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med 2000;191:435eC444.

    Iyoda T, Shimoyama S, Liu K, Omatsu Y, Akiyama Y, Maeda Y, Takahara K, Steinman RM, Inaba K. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 2002;195:1289eC1302.

    Scheinecker C, McHugh R, Shevach EM, Germain RN. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 2002;196:1079eC1090.

    Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001;194:769eC779.

    Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol 2002;80:477eC483.

    Mougneau E, Hugues S, Glaichenhaus N. Antigen presentation by dendritic cells in vivo. J Exp Med 2002;196:1013eC1016.

    Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM. Immune tolerance after delivery of dying cells to dendritic cells in situ. J Exp Med 2002;196:1091eC1097.

    Dhulst AI, Vermaelen KY, Brusselle GG, Joos GF, Pauwels RA. Time course of cigarette smoke-induced pulmonary inflammation in mice. Eur Respir J 2005;26:204eC213.

    Maes T, Vermaelen K, Pauwels R. Cigarette-smoke induced pulmonary recruitment and activation of dendritic cells in mice is Toll-like receptor 4 dependent. Eighth International Symposium on Dendritic Cells, Bruges, Belgium, 2004.

    Zhou LJ, Tedder TF. Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol 1995;154:3821eC3835.

    Mosialos G, Birkenbach M, Ayehunie S, Matsumura F, Pinkus GS, Kieff E, Langhoff E. Circulating human dendritic cells differentially express high levels of a 55-kd actin-bundling protein. Am J Pathol 1996;148:593eC600.

    Ross R, Jonuleit H, Bros M, Ross XL, Yamashiro S, Matsumura F, Enk AH, Knop J, Reske-Kunz AB. Expression of the actin-bundling protein fascin in cultured human dendritic cells correlates with dendritic morphology and cell differentiation. J Invest Dermatol 2000;115:658eC663.

    de Saint-Vis B, Vincent J, Vandenabeele S, Vanbervliet B, Pin JJ, Ait-Yahia S, Patel S, Mattei MG, Banchereau J, Zurawski S, et al. A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment. Immunity 1998;9:325eC336.

    Spits H, Couwenberg F, Bakker AQ, Weijer K, Uittenbogaart CH. Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1: evidence for a lymphoid origin of pre-DC2. J Exp Med 2000;192:1775eC1784.

    Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 1997;185:1101eC1111.

    Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 2000;165:6037eC6046.

    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ. Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194:863eC869.

    Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002;23:509eC512.

    Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284:1835eC1837.

    Anjuere F, del Hoyo GM, Martin P, Ardavin C. Langerhans cells develop from a lymphoid-committed precursor. Blood 2000;96:1633eC1637.

    Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C, Jorgas T, Kurz SM, Rose-John S, Yokota Y, et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol 2003;4:380eC386.

    Zhang Y, Zhang YY, Ogata M, Chen P, Harada A, Hashimoto S, Matsushima K. Transforming growth factor-beta1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway. Blood 1999;93:1208eC1220.

    Katz SI, Tamaki K, Sachs DH. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 1979;282:324eC326.

    Rowden G, Lewis MG, Sullivan AK. Ia antigen expression on human epidermal Langerhans cells. Nature 1977;268:247eC248.

    Caux C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, de Saint-Vis B, Jacquet C, Yoneda K, Imamura S, Schmitt D, Banchereau J. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J Exp Med 1996;184:695eC706.

    Valladeau J, Duvert-Frances V, Pin JJ, Dezutter-Dambuyant C, Vincent C, Massacrier C, Vincent J, Yoneda K, Banchereau J, Caux C, et al. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur J Immunol 1999;29:2695eC2704.

    Caux C, Massacrier C, Vanbervliet B, Dubois B, Durand I, Cella M, Lanzavecchia A, Banchereau J. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II. Functional analysis. Blood 1997;90:1458eC1470.

    van Haarst JM, Hoogsteden HC, de Wit HJ, Verhoeven GT, Havenith CE, Drexhage HA. Dendritic cells and their precursors isolated from human bronchoalveolar lavage: immunocytologic and functional properties. Am J Respir Cell Mol Biol 1994;11:344eC350.

    Havenith CE, Breedijk AJ, van Miert PP, Blijleven N, Calame W, Beelen RH, Hoefsmit EC. Separation of alveolar macrophages and dendritic cells via autofluorescence: phenotypical and functional characterization. J Leukoc Biol 1993;53:504eC510.

    Vermaelen K, Pauwels R. Accurate and simple discrimination of mouse pulmonary dendritic cell and macrophage populations by flow cytometry: methodology and new insights. Cytometry 2004;61A:170.

    van Haarst JM, Verhoeven GT, de Wit HJ, Hoogsteden HC, Debets R, Drexhage HA. CD1a+ and CD1a- accessory cells from human bronchoalveolar lavage differ in allostimulatory potential and cytokine production. Am J Respir Cell Mol Biol 1996;15:752eC759.

    Donnenberg VS, Donnenberg AD. Identification, rare-event detection and analysis of dendritic cell subsets in broncho-alveolar lavage fluid and peripheral blood by flow cytometry. Front Biosci 2003;8:s1175eCs1180.

    Bellini A, Vittori E, Marini M, Ackerman V, Mattoli S. Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. Chest 1993;103:997eC1005.

    Demedts IK, Brusselle GG, Vermaelen KY, Pauwels RA. Identification and characterization of human pulmonary dendritic cells. Am J Respir Cell Mol Biol 2005;32:177eC184.

    Schon-Hegrad MA, Oliver J, McMenamin PG, Holt PG. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)- bearing dendritic cells (DC) in the conducting airways. J Exp Med 1991;173:1345eC1356.

    Brokaw JJ, White GW, Baluk P, Anderson GP, Umemoto EY, McDonald DM. Glucocorticoid-induced apoptosis of dendritic cells in the rat tracheal mucosa. Am J Respir Cell Mol Biol 1998;19:598eC605.

    Lambrecht BN, Salomon B, Klatzmann D, Pauwels RA. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J Immunol 1998;160:4090eC4097.

    Holt PG, Schon-Hegrad MA. Localization of T cells, macrophages and dendritic cells in rat respiratory tract tissue: implications for immune function studies. Immunology 1987;62:349eC356.

    Cochand L, Isler P, Songeon F, Nicod LP. Human lung dendritic cells have an immature phenotype with efficient mannose receptors. Am J Respir Cell Mol Biol 1999;21:547eC554.

    Holt PG, Haining S, Nelson DJ, Sedgwick JD. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol 1994;153:256eC261.

    Nelson DJ, McMenamin C, McWilliam AS, Brenan M, Holt PG. Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia)-negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med 1994;179:203eC212.

    McWilliam AS, Nelson D, Thomas JA, Holt PG. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med 1994;179:1331eC1336.

    McWilliam AS, Marsh AM, Holt PG. Inflammatory infiltration of the upper airway epithelium during Sendai virus infection: involvement of epithelial dendritic cells. J Virol 1997;71:226eC236.

    Beyer M, Bartz H, Horner K, Doths S, Koerner-Rettberg C, Schwarze J. Sustained increases in numbers of pulmonary dendritic cells after respiratory syncytial virus infection. J Allergy Clin Immunol 2004;113:127eC133.

    McWilliam AS, Napoli S, Marsh AM, Pemper FL, Nelson DJ, Pimm CL, Stumbles PA, Wells TN, Holt PG. Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J Exp Med 1996;184:2429eC2432.

    Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:217eC242.

    Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol 1994;266:L278eCL286.

    Thorley AJ, Goldstraw P, Young A, Tetley TD. Primary human alveolar type II epithelial cell CCL20 (macrophage inflammatory protein-3)-induced dendritic cell migration. Am J Respir Cell Mol Biol 2005;32:262eC267.

    Abdelaziz MM, Devalia JL, Khair OA, Calderon M, Sapsford RJ, Davies RJ. The effect of conditioned medium from cultured human bronchial epithelial cells on eosinophil and neutrophil chemotaxis and adherence in vitro. Am J Respir Cell Mol Biol 1995;13:728eC737.

    Koyama S, Sato E, Nomura H, Kubo K, Nagai S, Izumi T. Type II pneumocytes release chemoattractant activity for monocytes constitutively. Am J Physiol 1997;272:L830eCL837.

    Koyama S, Sato E, Masubuchi T, Takamizawa A, Nomura H, Kubo K, Nagai S, Izumi T. Human lung fibroblasts release chemokinetic activity for monocytes constitutively. Am J Physiol 1998;275:L223eCL230.

    Godiska R, Chantry D, Raport CJ, Schweickart VL, Trong HL, Gray PW. Monocyte chemotactic protein-4: tissue-specific expression and signaling through CC chemokine receptor-2. J Leukoc Biol 1997;61:353eC360.

    Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 1996;184:1101eC1109.

    Gonzalo JA, Lloyd CM, Peled A, Delaney T, Coyle AJ, Gutierrez-Ramos JC. Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1 alpha in the inflammatory component of allergic airway disease. J Immunol 2000;165:499eC508.

    Vulcano M, Struyf S, Scapini P, Cassatella M, Bernasconi S, Bonecchi R, Calleri A, Penna G, Adorini L, Luini W, et al. Unique regulation of CCL18 production by maturing dendritic cells. J Immunol 2003;170:3843eC3849.

    Hieshima K, Imai T, Baba M, Shoudai K, Ishizuka K, Nakagawa T, Tsuruta J, Takeya M, Sakaki Y, Takatsuki K, et al. A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes. J Immunol 1997;159:1140eC1149.

    Schall T. Fractalkine: a strange attractor in the chemokine landscape. Immunol Today 1997;18:147.

    Papadopoulos EJ, Sassetti C, Saeki H, Yamada N, Kawamura T, Fitzhugh DJ, Saraf MA, Schall T, Blauvelt A, Rosen SD, et al. Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur J Immunol 1999;29:2551eC2559.

    Rothenberg ME, Luster AD, Lilly CM, Drazen JM, Leder P. Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung. J Exp Med 1995;181:1211eC1216.

    Cook EB, Stahl JL, Lilly CM, Haley KJ, Sanchez H, Luster AD, Graziano FM, Rothenberg ME. Epithelial cells are a major cellular source of the chemokine eotaxin in the guinea pig lung. Allergy Asthma Proc 1998;19:15eC22.

    Sabatini F, Silvestri M, Sale R, Scarso L, Defilippi AC, Risso FM, Rossi GA. Fibroblast-eosinophil interaction: modulation of adhesion molecules expression and chemokine release by human fetal lung fibroblasts in response to IL-4 and TNF-alpha. Immunol Lett 2002;84:173eC178.

    Yang Y, Loy J, Ryseck RP, Carrasco D, Bravo R. Antigen-induced eosinophilic lung inflammation develops in mice deficient in chemokine eotaxin. Blood 1998;92:3912eC3923.

    Rollins BJ. Chemokines. Blood 1997;90:909eC928.

    Power CA, Church DJ, Meyer A, Alouani S, Proudfoot AE, Clark-Lewis I, Sozzani S, Mantovani A, Wells TN. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells. J Exp Med 1997;186:825eC835.

    Stumbles PA, Strickland DH, Pimm CL, Proksch SF, Marsh AM, McWilliam AS, Bosco A, Tobagus I, Thomas JA, Napoli S, et al. Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus. J Immunol 2001;167:228eC234.

    Peters W, Cyster JG, Mack M, Schlondorff D, Wolf AJ, Ernst JD, Charo IF. CCR2-dependent trafficking of F4/80dim macrophages and CD11cdim/intermediate dendritic cells is crucial for T cell recruitment to lungs infected with Mycobacterium tuberculosis. J Immunol 2004;172:7647eC7653.

    Peters W, Scott HM, Chambers HF, Flynn JL, Charo IF, Ernst JD. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2001;98:7958eC7963.

    Cole AM, Waring AJ. The role of defensins in lung biology and therapy. Am J Respir Med 2002;1:249eC259.

    Harder J, Meyer-Hoffert U, Teran LM, Schwichtenberg L, Bartels J, Maune S, Schroder JM. Mucoid Pseudomonas aeruginosa, TNF-, and IL-1, but not IL-6, induce human -defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol 2000;22:714eC721.

    Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schroder JM, Wang JM, Howard OM, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999;286:525eC528.

    Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T. Airway epithelial cells release MIP-3/CCL20 in response to cytokines and ambient particulate matter. Am J Respir Cell Mol Biol 2003;28:648eC654.

    Lundy SK, Lira SA, Smit JJ, Cook DN, Berlin AA, Lukacs NW. Attenuation of allergen-induced responses in CCR6eC/eC mice is dependent upon altered pulmonary T lymphocyte activation. J Immunol 2005;174:2054eC2060.

    Suda T, McCarthy K, Vu Q, McCormack J, Schneeberger EE. Dendritic cell precursors are enriched in the vascular compartment of the lung. Am J Respir Cell Mol Biol 1998;19:728eC737.

    Coggle JE, Tarling JD. The proliferation kinetics of pulmonary alveolar macrophages. J Leukoc Biol 1984;35:317eC327.

    Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Engleman EG. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 2002;3:1135eC1141.

    Wang J, Snider DP, Hewlett BR, Lukacs NW, Gauldie J, Liang H, Xing Z. Transgenic expression of granulocyte-macrophage colony-stimulating factor induces the differentiation and activation of a novel dendritic cell population in the lung. Blood 2000;95:2337eC2345.

    Maraskovsky E, Daro E, Roux E, Teepe M, Maliszewski CR, Hoek J, Caron D, Lebsack ME, McKenna HJ. In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood 2000;96:878eC884.

    Masten BJ, Olson GK, Kusewitt DF, Lipscomb MF. Flt3 ligand preferentially increases the number of functionally active myeloid dendritic cells in the lungs of mice. J Immunol 2004;172:4077eC4083.

    Walzer T, Brawand P, Swart D, Tocker J, De Smedt T. No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand-deficient mice. J Allergy Clin Immunol 2005;115:192eC199.

    Engering A, Geijtenbeek TB, van Kooyk Y. Immune escape through C-type lectins on dendritic cells. Trends Immunol 2002;23:480eC485.

    Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 2003;197:121eC127.

    Serrano-Gomez D, Dominguez-Soto A, Ancochea J, Jimenez-Heffernan JA, Leal JA, Corbi AL. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus Conidia by dendritic cells and macrophages. J Immunol 2004;173:5635eC5643.

    Pollard AM, Lipscomb MF. Characterization of murine lung dendritic cells: similarities to Langerhans cells and thymic dendritic cells. J Exp Med 1990;172:159eC167.

    Vermaelen KY, Carro-Muino I, Lambrecht BN, Pauwels RA. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J Exp Med 2001;193:51eC60.

    Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001;2:361eC367.

    Xia W, Pinto CE, Kradin RL. The antigen-presenting activities of Ia+ dendritic cells shift dynamically from lung to lymph node after an airway challenge with soluble antigen. J Exp Med 1995;181:1275eC1283.

    Lambrecht BN, De Veerman M, Coyle AJ, Gutierrez-Ramos JC, Thielemans K, Pauwels RA. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J Clin Invest 2000;106:551eC559.

    Havenith CE, van Miert PP, Breedijk AJ, Beelen RH, Hoefsmit EC. Migration of dendritic cells into the draining lymph nodes of the lung after intratracheal instillation. Am J Respir Cell Mol Biol 1993;9:484eC488.

    Saeki H, Moore AM, Brown MJ, Hwang ST. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 1999;162:2472eC2475.

    Sozzani S, Allavena P, D'Amico G, Luini W, Bianchi G, Kataura M, Imai T, Yoshie O, Bonecchi R, Mantovani A. Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol 1998;161:1083eC1086.

    Yanagihara S, Komura E, Nagafune J, Watarai H, Yamaguchi Y. EBI1/CCR7 is a new member of dendritic cell chemokine receptor that is up-regulated upon maturation. J Immunol 1998;161:3096eC3102.

    Itakura M, Tokuda A, Kimura H, Nagai S, Yoneyama H, Onai N, Ishikawa S, Kuriyama T, Matsushima K. Blockade of secondary lymphoid tissue chemokine exacerbates Propionibacterium acnes-induced acute lung inflammation. J Immunol 2001;166:2071eC2079.

    Hammad H, Lambrecht BN, Pochard P, Gosset P, Marquillies P, Tonnel A-B, Pestel J. Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7. J Immunol 2002;169:1524eC1534.

    Robbiani DF, Finch RA, Jager D, Muller WA, Sartorelli AC, Randolph GJ. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 2000;103:757eC768.

    Scandella E, Men Y, Legler DF, Gillessen S, Prikler L, Ludewig B, Groettrup M. CCL19/CCL21-triggered signal transduction and migration of dendritic cells require prostaglandin E2. Blood 2003;103:1595eC1601.

    Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba K, Narumiya S. Prostaglandin E(2)-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Nat Med 2003;12:12.

    Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron M, Trottein F. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med 2001;193:1135eC1147.

    Angeli V, Hammad H, Staels B, Capron M, Lambrecht BN, Trottein F. Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol 2003;170:5295eC5301.

    Hammad H, Jan De Heer H, Soullie T, Hoogsteden HC, Trottein F, Lambrecht BN. Prostaglandin d(2) inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the d prostanoid receptor 1. J Immunol 2003;171:3936eC3940.

    Vermaelen K, Pauwels R. Accelerated airway dendritic cell maturation, trafficking, and elimination in a mouse model of asthma. Am J Respir Cell Mol Biol 2003;29:405eC409.

    Stumbles PA, Thomas JA, Pimm CL, Lee PT, Venaille TJ, Proksch S, Holt PG. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med 1998;188:2019eC2031.

    Dodge IL, Carr MW, Cernadas M, Brenner MB. IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. J Immunol 2003;170:4457eC4464.

    De Heer HJ, Hammad H, Soullie T, Hijdra D, Vos N, Willart MA, Hoogsteden HC, Lambrecht BN. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 2004;200:89eC98.

    Liu YJ. Uncover the mystery of plasmacytoid dendritic cell precursors or type 1 interferon producing cells by serendipity. Hum Immunol 2002;63:1067eC1071.

    Brimnes MK, Bonifaz L, Steinman RM, Moran TM. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein. J Exp Med 2003;198:133eC144.

    Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001;2:725eC731.

    Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002;8:1024eC1032.

    Legge KL, Braciale TJ. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. Immunity 2003;18:265eC277.

    Vu Q, McCarthy KM, McCormack JM, Schneeberger EE. Lung dendritic cells are primed by inhaled particulate antigens, and retain MHC class II/antigenic peptide complexes in hilar lymph nodes for a prolonged period of time. Immunology 2002;105:488eC498.

    Bozza S, Gaziano R, Spreca A, Bacci A, Montagnoli C, di Francesco P, Romani L. Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus. J Immunol 2002;168:1362eC1371.

    Holt PG, Degebrodt A, O'Leary C, Krska K, Plozza T. T cell activation by antigen-presenting cells from lung tissue digests: suppression by endogenous macrophages. Clin Exp Immunol 1985;62:586eC593.

    Holt PG, Oliver J, Bilyk N, McMenamin C, McMenamin PG, Kraal G, Thepen T. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. Cell Biol Int 1996;20:111eC120.

    Lipscomb MF, Pollard AM, Yates JL. A role for TGF-beta in the suppression by murine bronchoalveolar cells of lung dendritic cell initiated immune responses. Reg Immunol 1993;5:151eC157.

    Lee PT, Holt PG, McWilliam AS. Ontogeny of rat pulmonary alveolar macrophage function: evidence for a selective deficiency in IL-10 and nitric oxide production by newborn alveolar macrophages. Cytokine 2001;15:53eC57.

    Nicod LP, Galve-De-Rochemonteix B, Dayer JM. Modulation of IL-1 receptor antagonist and TNF-soluble receptors produced by alveolar macrophages and blood monocytes. Ann N Y Acad Sci 1994;725:323eC330.

    Kapsenberg ML, Teunissen MB, Stiekema FE, Keizer HG. Antigen-presenting cell function of dendritic cells and macrophages in proliferative T cell responses to soluble and particulate antigens. Eur J Immunol 1986;16:345eC350.

    Girvan A, Aldwell FE, Buchan GS, Faulkner L, Baird MA. Transfer of macrophage-derived mycobacterial antigens to dendritic cells can induce naive T-cell activation. Scand J Immunol 2003;57:107eC114.

    Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350eC362.

    Korsgren M, Erjefalt JS, Korsgren O, Sundler F, Persson CG. Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice. J Exp Med 1997;185:885eC892.

    Lambrecht BN, Peleman RA, Bullock GR, Pauwels RA. Sensitization to inhaled antigen by intratracheal instillation of dendritic cells. Clin Exp Allergy 2000;30:214eC224.

    Lambrecht BN, Carro-Muino I, Vermaelen K, Pauwels RA. Allergen-induced changes in bone-marrow progenitor and airway dendritic cells in sensitized rats. Am J Respir Cell Mol Biol 1999;20:1165eC1174.

    Vermaelen KY, Cataldo D, Tournoy K, Maes T, Dhulst A, Louis R, Foidart JM, Noel A, Pauwels R. Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma. J Immunol 2003;171:1016eC1022.

    Van Rijt LS, Prins JB, Leenen PJ, Thielemans K, De Vries VC, Hoogsteden HC, Lambrecht BN. Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31hiLy-6Cneg bone marrow precursors in a mouse model of asthma. Blood 2002;100:3663eC3671.

    Ohkawara Y, Lei XF, Stampfli MR, Marshall JS, Xing Z, Jordana M. Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. Am J Respir Cell Mol Biol 1997;16:510eC520.

    Gajewska BU, Tafuri A, Swirski FK, Walker T, Johnson JR, Shea T, Shahinian A, Goncharova S, Mak TW, Stampfli MR, et al. B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance. J Immunol 2005;174:3000eC3005.

    Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J, Gray PW, Matsushima K, Yoshie O. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol 1999;11:81eC88.

    Huh JC, Strickland DH, Jahnsen FL, Turner DJ, Thomas JA, Napoli S, Tobagus I, Stumbles PA, Sly PD, Holt PG. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med 2003;198:19eC30.

    Julia V, Hessel EM, Malherbe L, Glaichenhaus N, O'Garra A, Coffman RL. A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. Immunity 2002;16:271eC283.

    Ichiyasu H, McCormack JM, McCarthy KM, Dombkowski D, Preffer FI, Schneeberger EE. Mmp-9 deficient dendritic cells have impaired migration through tracheal epithelial tight junctions. Am J Respir Cell Mol Biol 2003;30:761eC770.

    Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu YJ. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183eC1186.

    Boonstra A, Asselin-Paturel C, Gilliet M, Crain C, Trinchieri G, Liu YJ, O'Garra A. Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential Toll-like receptor ligation. J Exp Med 2003;197:101eC109.

    Kline JN, Krieg AM, Waldschmidt TJ, Ballas ZK, Jain V, Businga TR. CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma. J Allergy Clin Immunol 1999;104:1258eC1264.

    Farkas L, Kvale EO, Johansen FE, Jahnsen FL, Lund-Johansen F. Plasmacytoid dendritic cells activate allergen-specific TH2 memory cells: modulation by CpG oligodeoxynucleotides. J Allergy Clin Immunol 2004;114:436eC443.

    Upham JW, Denburg JA, O'Byrne PM. Rapid response of circulating myeloid dendritic cells to inhaled allergen in asthmatic subjects. Clin Exp Allergy 2002;32:818eC823.

    Jahnsen FL, Moloney ED, Hogan T, Upham JW, Burke CM, Holt PG. Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 2001;56:823eC826.

    Parameswaran K, Liang H, Fanat A, Watson R, Snider DP, O'Byrne PM. Role for cysteinyl leukotrienes in allergen-induced change in circulating dendritic cell number in asthma. J Allergy Clin Immunol 2004;114(1):73eC79.

    Moller GM, Overbeek SE, Van Helden-Meeuwsen CG, Van Haarst JM, Prens EP, Mulder PG, Postma DS, Hoogsteden HC. Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids. Clin Exp Allergy 1996;26:517eC524.

    Tunon-De-Lara JM, Redington AE, Bradding P, Church MK, Hartley JA, Semper AE, Holgate ST. Dendritic cells in normal and asthmatic airways: expression of the alpha subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI -alpha). Clin Exp Allergy 1996;26:648eC655.

    Ohtani T, Nakagawa S, Kurosawa M, Mizuashi M, Ozawa M, Aiba S. Cellular basis of the role of diesel exhaust particles in inducing Th2-dominant response. J Immunol 2005;174:2412eC2419.

    Sagai M, Saito H, Ichinose T, Kodama M, Mori Y. Biological effects of diesel exhaust particles: I. In vitro production of superoxide and in vivo toxicity in mouse. Free Radic Biol Med 1993;14:37eC47.

    Traidl-Hoffmann C, Mariani V, Hochrein H, Karg K, Wagner H, Ring J, Mueller MJ, Jakob T, Behrendt H. Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization. J Exp Med 2005;201:627eC636.

    Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, Stewart GA, Taylor GW, Garrod DR, Cannell MB, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999;104:123eC133.

    Pichavant M, Charbonnier AS, Taront S, Brichet A, Wallaert B, Pestel J, Tonnel AB, Gosset P. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J Allergy Clin Immunol 2005;115:771eC778.

    Saeki S, Matsuse H, Kondo Y, Machida I, Kawano T, Tomari S, Obase Y, Fukushima C, Kohno S. Effects of antiasthmatic agents on the functions of peripheral blood monocyte-derived dendritic cells from atopic patients. J Allergy Clin Immunol 2004;114:538eC544.

    Charbonnier AS, Hammad H, Gosset P, Stewart GA, Alkan S, Tonnel AB, Pestel J. Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response. J Leukoc Biol 2003;73:91eC99.

    Hammad H, Smits HH, Ratajczak C, Nithiananthan A, Wierenga EA, Stewart GA, Jacquet A, Tonnel AB, Pestel J. Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22. Eur Cytokine Netw 2003;14:219eC228.

    Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001;1:69eC75.

    Nelson DJ, Holt PG. Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local dendritic cells to activation signals. J Immunol 1995;155:3517eC3524.

    Langrish CL, Buddle JC, Thrasher AJ, Goldblatt D. Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin Exp Immunol 2002;128:118eC123.

    Holt PG. Programming for responsiveness to environmental antigens that trigger allergic respiratory disease in adulthood is initiated during the perinatal period. Environ Health Perspect 1998;106:795eC800.

    Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 2002;196:1645eC1651.

    Kuipers H, Hijdra D, De Vries VC, Hammad H, Prins JB, Coyle AJ, Hoogsteden HC, Lambrecht BN. Lipopolysaccharide-induced suppression of airway Th2 responses does not require IL-12 production by dendritic cells. J Immunol 2003;171:3645eC3654.

    Gereda JE, Leung DY, Thatayatikom A, Streib JE, Price MR, Klinnert MD, Liu AH. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 2000;355:1680eC1683.

    Kondo Y, Matsuse H, Machida I, Kawano T, Saeki S, Tomari S, Obase Y, Fukushima C, Kohno S. Regulation of mite allergen-pulsed murine dendritic cells by respiratory syncytial virus. Am J Respir Crit Care Med 2004;169:494eC498.

    Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. Dendritic cells, obtained from peripheral blood precursors in the presence of PGE2, promote Th2 responses. Adv Exp Med Biol 1997;417:363eC367.

    Caron G, Delneste Y, Roelandts E, Duez C, Bonnefoy JY, Pestel J, Jeannin P. Histamine polarizes human dendritic cells into Th2 cell-promoting effector dendritic cells. J Immunol 2001;167:3682eC3686.

    Mazzoni A, Young HA, Spitzer JH, Visintin A, Segal DM. Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. J Clin Invest 2001;108:1865eC1873.

    Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child. Pediatr Allergy Immunol 1998;9:116eC124.

    Stampfli MR, Wiley RE, Neigh GS, Gajewska BU, Lei XF, Snider DP, Xing Z, Jordana M. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Invest 1998;102:1704eC1714.

    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673eC680.

    Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645eC2653.

    Zeid NA, Muller HK. Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells. Pathology 1995;27:247eC254.

    Robbins CS, Dawe DE, Goncharova SI, Pouladi MA, Drannik AG, Swirski FK, Cox G, Stampfli MR. Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. Am J Respir Cell Mol Biol 2004;30:202eC211.

    Hoogsteden HC, Verhoeven GT, Lambrecht BN, Prins JB. Airway inflammation in asthma and chronic obstructive pulmonary disease with special emphasis on the antigen-presenting dendritic cell: influence of treatment with fluticasone propionate. Eur J Immunol 1999;29:3815eC3825. [Published erratum appears in Clin Exp Allergy 2000;30(1):152.]

    Casolaro MA, Bernaudin JF, Saltini C, Ferrans VJ, Crystal RG. Accumulation of Langerhans' cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking. Am Rev Respir Dis 1988;137:406eC411.

    Soler P, Moreau A, Basset F, Hance AJ. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/Langerhans cells. Am Rev Respir Dis 1989;139:1112eC1117.

    Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469eC473.

    Matsuse T, Hayashi S, Kuwano K, Keunecke H, Jefferies WA, Hogg JC. Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am Rev Respir Dis 1992;146:177eC184.

    Liu AN, Mohammed AZ, Rice WR, Fiedeldey DT, Liebermann JS, Whitsett JA, Braciale TJ, Enelow RI. Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am J Respir Cell Mol Biol 1999;20:849eC858.

    Heath WR, Carbone FR. Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 2001;1:126eC134.

    Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P, Geiger JD, Hanash S, Beretta L. Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics. J Biol Chem 2001;276:17920eC17931.

    Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:2002eC2004.

    Vuillemenot BR, Rodriguez JF, Hoyle GW. Lymphoid tissue and emphysema in the lungs of transgenic mice inducibly expressing tumor necrosis factor-alpha. Am J Respir Cell Mol Biol 2004;30:438eC448.

    Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530eC534.

    Cumberbatch M, Kimber I. Tumour necrosis factor-alpha is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization. Immunology 1995;84:31eC35.

    Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109eC1118.

    Hunninghake GW, Davidson JM, Rennard S, Szapiel S, Gadek JE, Crystal RG. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 1981;212:925eC927.

    Nezelof C, Basset F, Rousseau MF. Histiocytosis X histogenetic arguments for a Langerhans cell origin. Biomedicine 1973;18:365eC371.

    Auld D. Pathology of eosinophilic granuloma of the lung. AMA Arch Pathol 1957;63:113eC131.

    Smetana K Jr, Mericka O, Saeland S, Homolka J, Brabec J, Gabius HJ. Diagnostic relevance of Langerin detection in cells from bronchoalveolar lavage of patients with pulmonary Langerhans cell histiocytosis, sarcoidosis and idiopathic pulmonary fibrosis. Virchows Arch 2004;444:171eC174.

    Dacic S, Trusky C, Bakker A, Finkelstein SD, Yousem SA. Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 2003;34:1345eC1349.

    Shamoto M. Mitotic histiocytes and intranuclear Langerhans cell granules in histiocytosis X. Virchows Arch B Cell Pathol 1977;24:87eC90.

    Schouten B, Egeler RM, Leenen PJ, Taminiau AH, Van Den Broek LJ, Hogendoorn PC. Expression of cell cycle-related gene products in langerhans cell histiocytosis. J Pediatr Hematol Oncol 2002;24:727eC732.

    Yu RC, Chu C, Buluwela L, Chu AC. Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 1994;343:767eC768.

    Brabencova E, Tazi A, Lorenzato M, Bonay M, Kambouchner M, Emile JF, Hance AJ, Soler P. Langerhans cells in Langerhans cell granulomatosis are not actively proliferating cells. Am J Pathol 1998;152:1143eC1149.

    Annels NE, Da Costa CE, Prins FA, Willemze A, Hogendoorn PC, Egeler RM. Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 2003;12:12.

    Geissmann F, Lepelletier Y, Fraitag S, Valladeau J, Bodemer C, Debre M, Leborgne M, Saeland S, Brousse N. Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 2001;97:1241eC1248.

    Tazi A, Moreau J, Bergeron A, Dominique S, Hance AJ, Soler P. Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 1999;163:3511eC3515.

    Tazi A, Bonay M, Bergeron A, Grandsaigne M, Hance AJ, Soler P. Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. Thorax 1996;51:611eC614.

    de Graaf JH, Tamminga RY, Dam-Meiring A, Kamps WA, Timens W. The presence of cytokines in Langerhans' cell histiocytosis. J Pathol 1996;180:400eC406.

    Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 1992;360:258eC261.

    Rolland A, Guyon L, Gill M, Cai YH, Banchereau J, McClain K, Palucka AK. Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis. J Immunol 2005;174:3067eC3071.

    Curti A, Fogli M, Ratta M, Tura S, Lemoli RM. Stem cell factor and FLT3-ligand are strictly required to sustain the long-term expansion of primitive CD34+DR-dendritic cell precursors. J Immunol 2001;166:848eC854.

    Asakura S, Colby TV, Limper AH. Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 1996;154:1525eC1530.

    Geissmann F, Prost C, Monnet JP, Dy M, Brousse N, Hermine O. Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J Exp Med 1998;187:961eC966.

    Hayashi T, Rush WL, Travis WD, Liotta LA, Stetler-Stevenson WG, Ferrans VJ. Immunohistochemical study of matrix metalloproteinases and their tissue inhibitors in pulmonary Langerhans' cell granulomatosis. Arch Pathol Lab Med 1997;121:930eC937.

    Noirey N, Staquet MJ, Gariazzo MJ, Serres M, Andre C, Schmitt D, Vincent C. Relationship between expression of matrix metalloproteinases and migration of epidermal and in vitro generated Langerhans cells. Eur J Cell Biol 2002;81:383eC389.

    Mautino G, Henriquet C, Gougat C, Le Cam A, Dayer JM, Bousquet J, Capony F. Increased expression of tissue inhibitor of metalloproteinase-1 and loss of correlation with matrix metalloproteinase-9 by macrophages in asthma. Lab Invest 1999;79:39eC47.

    Egeler RM, Favara BE, Laman JD, Claassen E. Abundant expression of CD40 and CD40-ligand (CD154) in paediatric Langerhans cell histiocytosis lesions. Eur J Cancer 2000;36:2105eC2110.

    Youkeles LH, Grizzanti JN, Liao Z, Chang CJ, Rosenstreich DL. Decreased tobacco-glycoprotein-induced lymphocyte proliferation in vitro in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 1995;151:145eC150.

    O'Sullivan BJ, Thomas R. CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-kappaB. J Immunol 2002;168:5491eC5498.

    Gilliet M, Soumelis V, Watanabe N, Hanabuchi S, Antonenko S, De Waal-Malefyt R, Liu YJ. Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. J Exp Med 2003;197:1059eC1063.

    Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996;2:1096eC1103.

    Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224eC1232.

    Inoshima N, Nakanishi Y, Minami T, Izumi M, Takayama K, Yoshino I, Hara N. The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognosis of non-small cell lung cancer. Clin Cancer Res 2002;8:3480eC3486.

    Colasante A, Castrilli G, Aiello FB, Brunetti M, Musiani P. Role of cytokines in distribution and differentiation of dendritic cell/Langerhans' cell lineage in human primary carcinomas of the lung. Hum Pathol 1995;26:866eC872.

    Tazi A, Bouchonnet F, Grandsaigne M, Boumsell L, Hance AJ, Soler P. Evidence that granulocyte macrophage-colony-stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancers. J Clin Invest 1993;91:566eC576.

    Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, Feng L, Hong WK, Xu XC. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001;7:861eC867.

    Marrogi AJ, Travis WD, Welsh JA, Khan MA, Rahim H, Tazelaar H, Pairolero P, Trastek V, Jett J, Caporaso NE, et al. Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma. Clin Cancer Res 2000;6:4739eC4744.

    Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y, Huang M, et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 2003;9:961eC968.

    Yang L, Yamagata N, Yadav R, Brandon S, Courtney RL, Morrow JD, Shyr Y, Boothby M, Joyce S, Carbone DP, et al. Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest 2003;111:727eC735.

    Makarenkova VP, Shurin GV, Tourkova IL, Balkir L, Pirtskhalaishvili G, Perez L, Gerein V, Siegfried JM, Shurin MR. Lung cancer-derived bombesin-like peptides down-regulate the generation and function of human dendritic cells. J Neuroimmunol 2003;145:55eC67.

    Tabarkiewicz J, Wojas K, Rolinski J. BDCA-1 positive cells and BDCA-2 positive cells in peripheral blood, metastatic lymph nodes and cancer tissue in patients with noneCsmall cell lung cancer. Seventh International Symposium on Dendritic Cells; 2002; Bamberg, Germany.

    Weynants P, Wauters P, Coulie PG, Van den Eynde B, Symann M, Boon T. Cytolytic response of human T cells against allogeneic small cell lung carcinoma treated with interferon gamma. Cancer Immunol Immunother 1988;27:228eC232.

    Gilliet M, Liu YJ. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 2002;195:695eC704.

    Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004;114:280eC290.

    Vicari AP, Vanbervliet B, Massacrier C, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, et al. In vivo manipulation of dendritic cell migration and activation to elicit antitumour immunity. Novartis Found Symp 2004;256:241eC254. [Discussion: 254eC629.]

    Hillinger S, Yang SC, Zhu L, Huang M, Duckett R, Atianzar K, Batra RK, Strieter RM, Dubinett SM, Sharma S. EBV-induced molecule 1 ligand chemokine (ELC/CCL19) promotes IFN-gamma-dependent antitumor responses in a lung cancer model. J Immunol 2003;171:6457eC6465.

    Trulock EP, Edwards LB, Taylor DO, Boucek MM, Mohacsi PJ, Keck BM, Hertz MI. The registry of the International Society for Heart and Lung Transplantation: twentieth official adult lung and heart-lung transplant report—2003. J Heart Lung Transplant 2003;22:625eC635.

    Starzl TE, Murase N, Thomson A, Demetris AJ, Qian S, Rao AS, Fung JJ. The bidirectional paradigm of transplant immunology. Ann N Y Acad Sci 1995;770:165eC176.

    Ruggiero R, Muz J, Fietsam R Jr, Thomas GA, Welsh RJ, Miller JE, Stephenson LW, Baciewicz FA Jr. Reestablishment of lymphatic drainage after canine lung transplantation. J Thorac Cardiovasc Surg 1993;106:167eC171.

    Milne DS, Gascoigne AD, Coaker J, Sviland L, Ashcroft T, Malcolm AJ, Corris PA. Mononuclear phagocyte populations in the transplanted human lung. Transplantation 1998;66:671eC673.

    Yousem SA, Ray L, Paradis IL, Dauber JA, Griffith BP. Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation. Ann Thorac Surg 1990;49:424eC428.

    Leonard CT, Soccal PM, Singer L, Berry GJ, Theodore J, Holt PG, Doyle RL, Rosen GD. Dendritic cells and macrophages in lung allografts: a role in chronic rejection Am J Respir Crit Care Med 2000;161:1349eC1354.

    Uyama T, Winter JB, Sakiyama S, Monden Y, Groen G, Prop J. Replacement of dendritic cells in the airways of rat lung allografts. Am Rev Respir Dis 1993;148:760eC767.

    Reinsmoen NL, Jackson A, McSherry C, Ninova D, Wiesner RH, Kondo M, Krom RA, Hertz MI, Bolman RM III, Matas AJ. Organ-specific patterns of donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in lung, kidney, and liver transplant recipients. Transplantation 1995;60:1546eC1554.

    McSherry C, Jackson A, Hertz MI, Bolman RM III, Savik K, Reinsmoen NL. Sequential measurement of peripheral blood allogeneic microchimerism levels and association with pulmonary function. Transplantation 1996;62:1811eC1818.

    Thomson AW, Lu L. Are dendritic cells the key to liver transplant tolerance Immunol Today 1999;20:27eC32.

    Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand- induced apoptosis. J Exp Med 1996;183:1789eC1796.

    Min WP, Gorczynski R, Huang XY, Kushida M, Kim P, Obataki M, Lei J, Suri RM, Cattral MS. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. J Immunol 2000;164:161eC167.

    Buonocore S, Paulart F, Le Moine A, Braun M, Salmon I, Van Meirvenne S, Thielemans K, Goldman M, Flamand V. Dendritic cells overexpressing CD95 (Fas) ligand elicit vigorous allospecific T-cell responses in vivo. Blood 2003;101:1469eC1476.

    Buonocore S, Flamand V, Claessen N, Heeringa P, Goldman M, Florquin S. Dendritic cells overexpressing Fas-ligand induce pulmonary vasculitis in mice. Clin Exp Immunol 2004;137:74eC80.

    Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, Hong X, Thomas D, Fechner JH Jr, Knechtle SJ. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997;94:8789eC8794.

    Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C, Cho HR, Aruffo A, Hollenbaugh D, Linsley PS, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996;381:434eC438.

    Rifle G, Mousson C. Dendritic cells and second signal blockade: a step toward allograft tolerance Transplantation 2002;73:S1eCS2.

    Swanson KA, Zheng Y, Heidler KM, Mizobuchi T, Wilkes DS. CD11c+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase. Am J Respir Cell Mol Biol 2004;30:311eC318.

    Jonuleit H, Schmitt E. The regulatory T cell family: distinct subsets and their interrelations. J Immunol 2003;171:6323eC6327.

    Nicod LP, el Habre F, Dayer JM, Boehringer N. Interleukin-10 decreases tumor necrosis factor alpha and beta in alloreactions induced by human lung dendritic cells and macrophages. Am J Respir Cell Mol Biol 1995;13:83eC90.

    Boehler A, Chamberlain D, Xing Z, Slutsky AS, Jordana M, Gauldie J, Liu M, Keshavjee S. Adenovirus-mediated interleukin-10 gene transfer inhibits post-transplant fibrous airway obliteration in an animal model of bronchiolitis obliterans. Hum Gene Ther 1998;9:541eC551.

    Meloni F, Vitulo P, Bianco AM, Paschetto E, Morosini M, Cascina A, Mazzucchelli I, Ciardelli L, Oggionni T, Fietta AM, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation 2004;77:762eC766.

    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151eC1164.

    Soulillou JP, Jacques Y. Monoclonal anti-IL2-receptor in organ transplantation. Transpl Int 1989;2:46eC52.

    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001;1:135eC145.

    Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 2000;12:1539eC1546.

    Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 2002;298:1025eC1029.

    Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, Simon JC. Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 2000;165:1863eC1870.

    Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF III. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 2001;276:10229eC10233.

    Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol 2002;168:5233eC5239.(Karim Vermaelen and Romai)

    http://www.100md.com/html/DirDu/2006/10/17/25/95/78.htm