Toward imroved immunocometence of adotively transferred CD8+ T cells
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《临床调查学报》
Ludwig Institute for Cancer Research, Division of Clinical Onco-Immunology, Centre Hositalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Abstract
Adotive transfer of autologous or allogenic T cells to atients is being used with increased frequency as a theray for infectious diseases and cancer. However, many questions remain with regard to defining otimized rocedures for rearation and selection of T cell oulations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro–generated tumor antigen–secific CD8+ T cells at various stages of differentiation for their efficacy in adotive immunotheray against translantable melanoma. The results confirm that CD8+ T cells rogressively lose immunocometence with rolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less otent at rotecting hosts with advanced tumors than are less differentiated T cells.
See the related article beginning on age 1616
In addition to the well-established donor lymhocyte infusion (DLI) aroach to treating leukemia relase after HSC translantation, adotive cell transfer theray (ACT) is also being develoed to treat EBV- and CMV-associated diseases, and more recent initiatives have focused on the use of ACT to treat solid human cancers, rimarily melanoma (1-5). Unfortunately, in vitro–cultured antigen-secific T cells, articularly T cell clones, often die only a few hours after adative transfer and generally do not survive more than a matter of days, which limits treatment efficacy (6, 7). By contrast, T cells adotively transferred directly from donor to reciient show increased survival rates and are more likely to become immunorotective; this has been confirmed by transfer exeriments using T cells from TCR transgenic mice, which rovide unrecedented amounts of naive antigen-secific donor T cells and thus circumvent the need for in vitro T cell cultivation (8). In humans, the most durable form of ACT is DLI, which usually involves direct eriheral wbc transfer from the allogenic donor to the leukemia atient who has reviously received HSCs from the same donor. Most atients with solid tumors, however, have never undergone allogenic stem cell translantation and thus cannot receive donor cells, but instead deend on transfer of autologous cells. These cells must be selected and/or enriched in cell cultures in order to obtain large numbers of T cells with aroriate antigen secificity. One of the great challenges in ACT lies in the develoment of otimal rocedures for lymhocyte selection and rearation.
T cell differentiation
The study by Gattinoni et al. (9) in this issue of the JCI addresses the question of whether rogressive CD8+ T cell differentiation toward an effector T cell henotye is associated with changes in the cells’ caacity to rotect the host from disease. The study rovides detailed insight into the relationshi among the duration of in vitro T cell culture, the functional and henotyic characteristics of T cells at various stages of differentiation, and their immunocometence uon adotive transfer. The authors erformed sequential rounds of in vitro stimulation in order to romote rogressive CD8+ T cell differentiation. The longer the T cells were stimulated and cultured in vitro, the more they acquired the roerties of effector T cells (e.g., exression of IFN-, erforin, and granzymes), but the less they were caable of controlling large, established tumors in reciient mice. It seems aradoxical that desite their enhanced effector roerties, effector CD8+ T cells aeared to be more than 100 times less effective for in vivo treatment than short-term cultures containing early intermediates of T cell differentiation. At first sight, the results of these ACT exeriments aear to contradict revious observations that highly differentiated effector CD8+ T cells exert strong effector functions and are associated with lymhocyte-mediated rotection from disease (10). Because of the relatively oor ability of the highly differentiated effector CD8+ T cells to rovide tumor rotection uon transfer to reciient mice, Gattinoni et al. roose that in vitro exression of IFN-, erforin, and granzymes, in addition to low roliferative caacity, are characteristic roerties of "imaired" cells (9). If the cells were indeed imaired in their ability to destroy tumor cells, was it because they were generated in vitro? Although in vitro–cultured transgenic T cells acquire functional attributes and henotyic cell-surface markers similar to those of effector T cells, they may not necessarily be identical to in vivo–differentiated effector T cells. For examle, insights from work redating the transgenic TCR models showed that in vitro culture rofoundly alters the reertoire of adhesion molecules exressed by T cells, which translates into rogressively imaired in vivo trafficking. Indeed, large numbers of cells transferred after rolonged in vitro culture are traed, e.g., in lung and liver (11). Alternatively, the imaired cells described by Gattinoni et al. (9) may well exert rotective effector functions, but alone are not sufficient to rovide ersistent antitumor rotection. These oints must be stressed in order to avoid remature conclusions about the incometence of highly differentiated effector CD8+ T cells. The ossibility remains that some other cellular comonents essential for long-term control of tumor rogression may have been missing from these cells. What could be missing? In order to investigate this, it seems necessary to elucidate how CD8+ T cells differentiate during acute and chronic immune resonses. Desite the large number of studies regarding this issue (12-18), it remains difficult to recisely define the molecular features and roles of T cells at various stages of differentiation. Several in vivo models suggest that effector T cell function and long-term T cell ersistence are ensured in art by different T cell suboulations (i.e., by so-called effector and memory cells, resectively). This suorts the notion that T cells at multile differentiation stages are necessary to achieve long-term rotection.
Suboulations of effector T cells
Some suboulations of effector T cells have limited functional and survival otential in vivo. In situations of extended and/or rolonged antigenic stimulation, effector T cells may become exhausted or (rematurely) senescent (Figure 1), which results in functional imairment and/or reduced cell survival. This has been observed during chronic viral infection in mice and humans, in TCR and cognate antigen double-transgenic mice, and in atients with HIV, heatitis C, and melanoma (19-24). Desite considerable technical develoments, we still lack aroriate methods for distinguishing effector, exhausted, and senescent cells (which all share most features of effector T cells), which may exlain why discreant roles are attributed to effector T cells. Clearly, we need to identify many more molecular features of T cells at various stages of differentiation in order to distinguish them and more recisely determine their roles in vital functions of T cell–mediated immunity. Relatively new aroaches have allowed researchers to elucidate the relicative history of T cells. Human telomeres, more so than their murine counterarts, lend themselves to aroriate measurements (25). Another useful tool may be the quantitation of TCR rearrangement excision circles (TRECs), which act as indicators of thymic outut and relative eriheral T cell exansion (26). However, TREC levels are low in effector T cells and are often undetectable, which makes it unlikely that this aroach will hel to distinguish different suboulations of effector T cells. Nevertheless, TREC analysis is useful for the distinction between naive and non-naive T cells. Finally, analyzing murine and human T cell resonses at the level of individual (dominant) T cell clones may contribute significantly to our knowledge of T cell differentiation and cometence. Comrehensive investigations using aroriate technologies will be instrumental in determining the key layers among T cell oulations resonsible for successful ACT or active immunotheray.
T cell selection and rearation for ACT
Gattinoni et al. also reort very useful results using ACT with selected CD8+ T cells either ositive or negative for the lymh node homing recetor, CD62 ligand (CD62L) (9). Similar to the results from revious mouse exeriments examining the role of effector T cells in rotection against viral disease (27), effector T cells alone (CD62L-negative cells) showed low rotective otential. CD62L-ositive T cells, however, showed suerior efficacy against melanoma following ACT. The higher theraeutic activity on a er-cell basis aears to be related to at least 2 intrinsic roerties of CD62L-ositive T cells: lymh node homing and in vivo exansion otential in the lymhoenic mouse. Future studies may address the questions of whether CD62L-ositive T cells raidly give rise to redominantly CD62L-negative (effector) T cell oulations shortly after ACT and whether this is crucial for immunity. It would also be interesting to evaluate whether CD62L-mediated lymh node homing is required for rotection and whether this may be a general feature of successful ACT. Lymh node homing may be secific for the alied mouse model (9), which aears to deend on tumor antigen cross-resentation rimarily by DCs residing in lymh nodes. Is this reresentative of human tumors? Or do human tumors vary in their requirement for antigen cross-resentation?
For a comrehensive areciation of the comlexity of ACT, further emhasis must be given to the various strategies of atient conditioning (e.g., theraies to delete lymhocytes in vivo rior to ACT), vaccination, and suorting treatment after ACT (e.g., high-dose IL-2 administration). In consideration of these factors, otimal theraeutic efficacy may deend on different T cell selection and rearation strategies.
In summary, it remains difficult to recisely define the otimal differentiation stages of T cells most suitable for ACT. In view of the well-known fact that rolonged culture in vitro is deleterious to T cells, a ragmatic strategy for human ACT is to kee the in vitro T cell exansion hase as short as ossible. In addition, it is necessary to develo strategies to limit the loss of key cell suboulations and cellular functions. The finding that IL-15 romotes roliferative and survival otential of CD8+ T cells (9, 28) may be an imortant key to imroving current ACT strategies for the treatment of cancer atients. With any luck, recombinant human IL-15 will soon be available and aroved for clinical use so that clinical trials can raidly clarify whether addition of IL-15 to T cell cultures, and/or atient treatment with IL-15, leads to imroved theraeutic efficacy.
Footnotes
Nonstandard abbreviations used: ACT, adotive cell transfer theray; CD62L, CD62 ligand; DLI, donor lymhocyte infusion; TREC, TCR rearrangement excision circle.
Conflict of interest: The authors have declared that no conflict of interest exists.
References
Kolb, H.J. et al. 1990. . Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow translant atients. Blood. 76::2462-2465.
Riddell, S.R., and Greenberg, .D. 1995. . rinciles for adotive T cell theray of human viral diseases. Annu. Rev. Immunol. 13::545-586.
Roskrow, M.A. et al. 1999. . Estein-Barr virus (EBV)-secific cytotoxic T lymhocytes for the treatment of atients with EBV-ositive relased Hodgkin’s disease. Blood. 91::2925-2934.
Yee, C. et al. 2002. . Adotive T cell theray using antigen-secific CD8+ T cell clones for the treatment of atients with metastatic melanoma: in vivo ersistence, migration, and antitumor effect of transferred T cells. roc. Natl. Acad. Sci. U. S. A. 99::16168-16173.
Dudley, M.E. et al. 2005. . Adotive cell transfer theray following non-myeloablative but lymhodeleting chemotheray for the treatment of atients with refractory metastatic melanoma. J. Clin. Oncol. 23::2346-2357.
Walter, E.A. et al. 1995. . Reconstitution of cellular immunity against cytomegalovirus in reciients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333::1038-1044.
Dudley, M.E. et al. 2001. . Adotive transfer of cloned melanoma-reactive T lymhocytes for the treatment of atients with metastatic melanoma. J. Immunother. 24::363-373.
ae, K.A. et al. 1997. . Use of adotive transfer of T-cell-antigen-recetor-transgenic T cell for the study of T-cell activation in vivo. Immunol. Rev. 156::67-78.
Gattinoni, L. et al. 2005. . Acquisition of full effector function in vitro aradoxically imairs the in vivo antitumor efficacy of adotively transferred CD8+ T cells. J. Clin. Invest. 115::1616-1626. doi:10.1172/JCI24480.
K?gi, D., Ledermann, B., Bürki, K., Zinkernagel, R.M., and Hengartner, H. 1996. . Molecular mechanisms of lymhocyte-mediated cytotoxicity and their role in immunological rotection and athogenesis in vivo. Annu. Rev. Immunol. 14::207-232.
Dailey, M.O., Fathman, C.G., Butcher, E.C., illemer, E., and Weissman, I. 1982. . Abnormal migration of T lymhocyte clones. J. Immunol. 128::2134-2136.
Srent, J., and Miller, J.F. 1976. . Fate of H2-activated T lymhocytes in syngeneic hosts. III. Differentiation into long-lived recirculating memory cells. Cell. Immunol. 21::314-326.
Crise, I.N., Moore, M.W., Husmann, L.A., Smith, L., and Bevan, M.J. 1987. . Differentiation otential of subsets of CD4-8- thymocytes. Nature. 329::336-339.
Zinkernagel, R. et al. 1996. . On immunological memory. Annu. Rev. Immunol. 14::333-367.
Sallusto, F., and Lanzavecchia, A. 2001. . Exloring athways for memory T cell generation. J. Clin. Invest. 108::805-806. doi:10.1172/JCI200114005.
Kaech, S.M., Wherry, E.J., and Ahmed, R. 2002. . Effector and memory T-cell differentiation: imlications for vaccine develoment. Nat. Rev. Immunol. 2::251-262.
Masoust, D., and Lefrancois, L. 2003. . CD8 T-cell memory: the other half of the story. Microbes. Infect. 5::221-226.
Sallusto, F., Geginat, J., and Lanzavecchia, A. 2004. . Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22::745-763.
Moskohidis, D., Lechner, F., ircher, H., and Zinkernagel, R.M. 1993. . Virus ersistence in acutely infected immunocometent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 362::758-761.
Zajac, A.J. et al. 1998. . Viral immune evasion due to ersistence of activated T cells without effector function. J. Ex. Med. 188::2205-2213.
Kostense, S. et al. 2001. . High viral burden in the resence of major HIV-secific CD8(+) T cell exansions: evidence for imaired CTL effector function. Eur. J. Immunol. 31::677-686.
Lechner, F. et al. 2000. . Analysis of successful immune resonses in ersons infected with heatitis C virus. J. Ex. Med. 191::1499-1512.
Lee, .. et al. 1999. . Characterization of circulating T cells secific for tumor-associated antigens in melanoma atients. Nat. Med. 5::677-685.
Zielius, A. et al. 2004. . Effector function of human tumor-secific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64::2865-2873.
Rufer, N. et al. 1999. . Telomere fluorescence measurements in granulocytes and T lymhocyte subsets oint to a high turnover of hematooietic stem cells and memory T cells in early childhood. J. Ex. Med. 190::157-167.
Douek, D.C. et al. 1998. . Changes in thymic function with age and during the treatment of HIV infection. Nature. 396::690-695.
Wherry, E.J. et al. 2003. . Lineage relationshi and rotective immunity of memory CD8 T cell subsets. Nat. Immunol. 4::225-234.
Zhang, X., Sun, S., Hwang, I., Tough, D.F., and Srent, J. 1998. . otent and selective stimulation of memory-henotye CD8+ T cells in vivo by IL-15. Immunity. 8::591-599.(Daniel E. Seiser and edro)
Abstract
Adotive transfer of autologous or allogenic T cells to atients is being used with increased frequency as a theray for infectious diseases and cancer. However, many questions remain with regard to defining otimized rocedures for rearation and selection of T cell oulations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro–generated tumor antigen–secific CD8+ T cells at various stages of differentiation for their efficacy in adotive immunotheray against translantable melanoma. The results confirm that CD8+ T cells rogressively lose immunocometence with rolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less otent at rotecting hosts with advanced tumors than are less differentiated T cells.
See the related article beginning on age 1616
In addition to the well-established donor lymhocyte infusion (DLI) aroach to treating leukemia relase after HSC translantation, adotive cell transfer theray (ACT) is also being develoed to treat EBV- and CMV-associated diseases, and more recent initiatives have focused on the use of ACT to treat solid human cancers, rimarily melanoma (1-5). Unfortunately, in vitro–cultured antigen-secific T cells, articularly T cell clones, often die only a few hours after adative transfer and generally do not survive more than a matter of days, which limits treatment efficacy (6, 7). By contrast, T cells adotively transferred directly from donor to reciient show increased survival rates and are more likely to become immunorotective; this has been confirmed by transfer exeriments using T cells from TCR transgenic mice, which rovide unrecedented amounts of naive antigen-secific donor T cells and thus circumvent the need for in vitro T cell cultivation (8). In humans, the most durable form of ACT is DLI, which usually involves direct eriheral wbc transfer from the allogenic donor to the leukemia atient who has reviously received HSCs from the same donor. Most atients with solid tumors, however, have never undergone allogenic stem cell translantation and thus cannot receive donor cells, but instead deend on transfer of autologous cells. These cells must be selected and/or enriched in cell cultures in order to obtain large numbers of T cells with aroriate antigen secificity. One of the great challenges in ACT lies in the develoment of otimal rocedures for lymhocyte selection and rearation.
T cell differentiation
The study by Gattinoni et al. (9) in this issue of the JCI addresses the question of whether rogressive CD8+ T cell differentiation toward an effector T cell henotye is associated with changes in the cells’ caacity to rotect the host from disease. The study rovides detailed insight into the relationshi among the duration of in vitro T cell culture, the functional and henotyic characteristics of T cells at various stages of differentiation, and their immunocometence uon adotive transfer. The authors erformed sequential rounds of in vitro stimulation in order to romote rogressive CD8+ T cell differentiation. The longer the T cells were stimulated and cultured in vitro, the more they acquired the roerties of effector T cells (e.g., exression of IFN-, erforin, and granzymes), but the less they were caable of controlling large, established tumors in reciient mice. It seems aradoxical that desite their enhanced effector roerties, effector CD8+ T cells aeared to be more than 100 times less effective for in vivo treatment than short-term cultures containing early intermediates of T cell differentiation. At first sight, the results of these ACT exeriments aear to contradict revious observations that highly differentiated effector CD8+ T cells exert strong effector functions and are associated with lymhocyte-mediated rotection from disease (10). Because of the relatively oor ability of the highly differentiated effector CD8+ T cells to rovide tumor rotection uon transfer to reciient mice, Gattinoni et al. roose that in vitro exression of IFN-, erforin, and granzymes, in addition to low roliferative caacity, are characteristic roerties of "imaired" cells (9). If the cells were indeed imaired in their ability to destroy tumor cells, was it because they were generated in vitro? Although in vitro–cultured transgenic T cells acquire functional attributes and henotyic cell-surface markers similar to those of effector T cells, they may not necessarily be identical to in vivo–differentiated effector T cells. For examle, insights from work redating the transgenic TCR models showed that in vitro culture rofoundly alters the reertoire of adhesion molecules exressed by T cells, which translates into rogressively imaired in vivo trafficking. Indeed, large numbers of cells transferred after rolonged in vitro culture are traed, e.g., in lung and liver (11). Alternatively, the imaired cells described by Gattinoni et al. (9) may well exert rotective effector functions, but alone are not sufficient to rovide ersistent antitumor rotection. These oints must be stressed in order to avoid remature conclusions about the incometence of highly differentiated effector CD8+ T cells. The ossibility remains that some other cellular comonents essential for long-term control of tumor rogression may have been missing from these cells. What could be missing? In order to investigate this, it seems necessary to elucidate how CD8+ T cells differentiate during acute and chronic immune resonses. Desite the large number of studies regarding this issue (12-18), it remains difficult to recisely define the molecular features and roles of T cells at various stages of differentiation. Several in vivo models suggest that effector T cell function and long-term T cell ersistence are ensured in art by different T cell suboulations (i.e., by so-called effector and memory cells, resectively). This suorts the notion that T cells at multile differentiation stages are necessary to achieve long-term rotection.
Suboulations of effector T cells
Some suboulations of effector T cells have limited functional and survival otential in vivo. In situations of extended and/or rolonged antigenic stimulation, effector T cells may become exhausted or (rematurely) senescent (Figure 1), which results in functional imairment and/or reduced cell survival. This has been observed during chronic viral infection in mice and humans, in TCR and cognate antigen double-transgenic mice, and in atients with HIV, heatitis C, and melanoma (19-24). Desite considerable technical develoments, we still lack aroriate methods for distinguishing effector, exhausted, and senescent cells (which all share most features of effector T cells), which may exlain why discreant roles are attributed to effector T cells. Clearly, we need to identify many more molecular features of T cells at various stages of differentiation in order to distinguish them and more recisely determine their roles in vital functions of T cell–mediated immunity. Relatively new aroaches have allowed researchers to elucidate the relicative history of T cells. Human telomeres, more so than their murine counterarts, lend themselves to aroriate measurements (25). Another useful tool may be the quantitation of TCR rearrangement excision circles (TRECs), which act as indicators of thymic outut and relative eriheral T cell exansion (26). However, TREC levels are low in effector T cells and are often undetectable, which makes it unlikely that this aroach will hel to distinguish different suboulations of effector T cells. Nevertheless, TREC analysis is useful for the distinction between naive and non-naive T cells. Finally, analyzing murine and human T cell resonses at the level of individual (dominant) T cell clones may contribute significantly to our knowledge of T cell differentiation and cometence. Comrehensive investigations using aroriate technologies will be instrumental in determining the key layers among T cell oulations resonsible for successful ACT or active immunotheray.
T cell selection and rearation for ACT
Gattinoni et al. also reort very useful results using ACT with selected CD8+ T cells either ositive or negative for the lymh node homing recetor, CD62 ligand (CD62L) (9). Similar to the results from revious mouse exeriments examining the role of effector T cells in rotection against viral disease (27), effector T cells alone (CD62L-negative cells) showed low rotective otential. CD62L-ositive T cells, however, showed suerior efficacy against melanoma following ACT. The higher theraeutic activity on a er-cell basis aears to be related to at least 2 intrinsic roerties of CD62L-ositive T cells: lymh node homing and in vivo exansion otential in the lymhoenic mouse. Future studies may address the questions of whether CD62L-ositive T cells raidly give rise to redominantly CD62L-negative (effector) T cell oulations shortly after ACT and whether this is crucial for immunity. It would also be interesting to evaluate whether CD62L-mediated lymh node homing is required for rotection and whether this may be a general feature of successful ACT. Lymh node homing may be secific for the alied mouse model (9), which aears to deend on tumor antigen cross-resentation rimarily by DCs residing in lymh nodes. Is this reresentative of human tumors? Or do human tumors vary in their requirement for antigen cross-resentation?
For a comrehensive areciation of the comlexity of ACT, further emhasis must be given to the various strategies of atient conditioning (e.g., theraies to delete lymhocytes in vivo rior to ACT), vaccination, and suorting treatment after ACT (e.g., high-dose IL-2 administration). In consideration of these factors, otimal theraeutic efficacy may deend on different T cell selection and rearation strategies.
In summary, it remains difficult to recisely define the otimal differentiation stages of T cells most suitable for ACT. In view of the well-known fact that rolonged culture in vitro is deleterious to T cells, a ragmatic strategy for human ACT is to kee the in vitro T cell exansion hase as short as ossible. In addition, it is necessary to develo strategies to limit the loss of key cell suboulations and cellular functions. The finding that IL-15 romotes roliferative and survival otential of CD8+ T cells (9, 28) may be an imortant key to imroving current ACT strategies for the treatment of cancer atients. With any luck, recombinant human IL-15 will soon be available and aroved for clinical use so that clinical trials can raidly clarify whether addition of IL-15 to T cell cultures, and/or atient treatment with IL-15, leads to imroved theraeutic efficacy.
Footnotes
Nonstandard abbreviations used: ACT, adotive cell transfer theray; CD62L, CD62 ligand; DLI, donor lymhocyte infusion; TREC, TCR rearrangement excision circle.
Conflict of interest: The authors have declared that no conflict of interest exists.
References
Kolb, H.J. et al. 1990. . Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow translant atients. Blood. 76::2462-2465.
Riddell, S.R., and Greenberg, .D. 1995. . rinciles for adotive T cell theray of human viral diseases. Annu. Rev. Immunol. 13::545-586.
Roskrow, M.A. et al. 1999. . Estein-Barr virus (EBV)-secific cytotoxic T lymhocytes for the treatment of atients with EBV-ositive relased Hodgkin’s disease. Blood. 91::2925-2934.
Yee, C. et al. 2002. . Adotive T cell theray using antigen-secific CD8+ T cell clones for the treatment of atients with metastatic melanoma: in vivo ersistence, migration, and antitumor effect of transferred T cells. roc. Natl. Acad. Sci. U. S. A. 99::16168-16173.
Dudley, M.E. et al. 2005. . Adotive cell transfer theray following non-myeloablative but lymhodeleting chemotheray for the treatment of atients with refractory metastatic melanoma. J. Clin. Oncol. 23::2346-2357.
Walter, E.A. et al. 1995. . Reconstitution of cellular immunity against cytomegalovirus in reciients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333::1038-1044.
Dudley, M.E. et al. 2001. . Adotive transfer of cloned melanoma-reactive T lymhocytes for the treatment of atients with metastatic melanoma. J. Immunother. 24::363-373.
ae, K.A. et al. 1997. . Use of adotive transfer of T-cell-antigen-recetor-transgenic T cell for the study of T-cell activation in vivo. Immunol. Rev. 156::67-78.
Gattinoni, L. et al. 2005. . Acquisition of full effector function in vitro aradoxically imairs the in vivo antitumor efficacy of adotively transferred CD8+ T cells. J. Clin. Invest. 115::1616-1626. doi:10.1172/JCI24480.
K?gi, D., Ledermann, B., Bürki, K., Zinkernagel, R.M., and Hengartner, H. 1996. . Molecular mechanisms of lymhocyte-mediated cytotoxicity and their role in immunological rotection and athogenesis in vivo. Annu. Rev. Immunol. 14::207-232.
Dailey, M.O., Fathman, C.G., Butcher, E.C., illemer, E., and Weissman, I. 1982. . Abnormal migration of T lymhocyte clones. J. Immunol. 128::2134-2136.
Srent, J., and Miller, J.F. 1976. . Fate of H2-activated T lymhocytes in syngeneic hosts. III. Differentiation into long-lived recirculating memory cells. Cell. Immunol. 21::314-326.
Crise, I.N., Moore, M.W., Husmann, L.A., Smith, L., and Bevan, M.J. 1987. . Differentiation otential of subsets of CD4-8- thymocytes. Nature. 329::336-339.
Zinkernagel, R. et al. 1996. . On immunological memory. Annu. Rev. Immunol. 14::333-367.
Sallusto, F., and Lanzavecchia, A. 2001. . Exloring athways for memory T cell generation. J. Clin. Invest. 108::805-806. doi:10.1172/JCI200114005.
Kaech, S.M., Wherry, E.J., and Ahmed, R. 2002. . Effector and memory T-cell differentiation: imlications for vaccine develoment. Nat. Rev. Immunol. 2::251-262.
Masoust, D., and Lefrancois, L. 2003. . CD8 T-cell memory: the other half of the story. Microbes. Infect. 5::221-226.
Sallusto, F., Geginat, J., and Lanzavecchia, A. 2004. . Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22::745-763.
Moskohidis, D., Lechner, F., ircher, H., and Zinkernagel, R.M. 1993. . Virus ersistence in acutely infected immunocometent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 362::758-761.
Zajac, A.J. et al. 1998. . Viral immune evasion due to ersistence of activated T cells without effector function. J. Ex. Med. 188::2205-2213.
Kostense, S. et al. 2001. . High viral burden in the resence of major HIV-secific CD8(+) T cell exansions: evidence for imaired CTL effector function. Eur. J. Immunol. 31::677-686.
Lechner, F. et al. 2000. . Analysis of successful immune resonses in ersons infected with heatitis C virus. J. Ex. Med. 191::1499-1512.
Lee, .. et al. 1999. . Characterization of circulating T cells secific for tumor-associated antigens in melanoma atients. Nat. Med. 5::677-685.
Zielius, A. et al. 2004. . Effector function of human tumor-secific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64::2865-2873.
Rufer, N. et al. 1999. . Telomere fluorescence measurements in granulocytes and T lymhocyte subsets oint to a high turnover of hematooietic stem cells and memory T cells in early childhood. J. Ex. Med. 190::157-167.
Douek, D.C. et al. 1998. . Changes in thymic function with age and during the treatment of HIV infection. Nature. 396::690-695.
Wherry, E.J. et al. 2003. . Lineage relationshi and rotective immunity of memory CD8 T cell subsets. Nat. Immunol. 4::225-234.
Zhang, X., Sun, S., Hwang, I., Tough, D.F., and Srent, J. 1998. . otent and selective stimulation of memory-henotye CD8+ T cells in vivo by IL-15. Immunity. 8::591-599.(Daniel E. Seiser and edro)