Key Points
-
Common cytokine receptor γ-chain (γc) cytokines control the immune response at overlapping, as well as distinct, checkpoints, and the levels of expression of γc-cytokine receptors are differentially regulated during an immune response.
-
Interleukin-2 (IL-2), IL-7 and IL-15 exert diverse effects related to T-cell survival, activation and clonal expansion, and memory-cell development and maintenance.
-
IL-7 mediates the survival of naive and memory T cells.
-
Memory T-cell homeostasis can be affected by secondary encounter with antigen, bystander proliferation or attrition.
-
IL-15 is essential for the homeostatic proliferation of memory CD8+ T cells and maintenance of the steady-state level of CD8+ T-cell memory.
-
IL-15 might exert direct effects on memory CD8+ T cells or might act on other cell types, which subsequently regulate memory T-cell proliferation. IL-15 might also be presented by other cells to CD8+ T cells through interaction with the IL-15 receptor β-chain.
Abstract
Evidence has accumulated that cytokines have a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell from initial activation to memory-cell generation, indicating the checkpoints at which cytokines determine the fate of the T cell. Members of the common cytokine-receptor γ-chain (γc)-cytokine family — in particular, interleukin-7 (IL-7) and IL-15 — act at each stage of the immune response to promote proliferation and survival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagated and maintained.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cho, B. K., Wang, C., Sugawa, S., Eisen, H. N. & Chen, J. Functional differences between memory and naive CD8 T cells. Proc. Natl Acad. Sci. USA 96, 2976–2981 (1999).
Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
Kearney, E. R., Pape, K. A., Loh, D. Y. & Jenkins, M. K. Visualization of peptide-specific T-cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994).
Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
Lin, J. X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13 and IL-15. Immunity 2, 331–339 (1995).
Bulfone-Paus, S. et al. Death deflected: IL-15 inhibits TNF-α-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Rα chain. FASEB J. 13, 1575–1585 (1999).
Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).
Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin-15-deficient mice. J. Exp. Med. 191, 771–780 (2000). References 7 and 8 describe the phenotype of IL-15Rα-deficient mice and IL-15-deficient mice, respectively, and show that memory-phenotype CD8+ T cells are deficient in the absence of either IL-15Rα or IL-15.
Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nature Immunol. 2, 947–950 (2001).
Biron, C. A. Interferons α and β as immune regulators — a new look. Immunity 14, 661–664 (2001).
Mattei, F., Schiavoni, G., Belardelli, F. & Tough, D. F. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA or lipopolysaccharide and promotes dendritic-cell activation. J. Immunol. 167, 1179–1187 (2001).
Granucci, F. et al. Inducible IL-2 production by dendritic cells revealed by global gene-expression analysis. Nature Immunol. 2, 882–888 (2001).
Ohteki, T., Suzue, K., Maki, C., Ota, T. & Koyasu, S. Critical role of IL-15–IL-15R for antigen-presenting cell functions in the innate immune response. Nature Immunol. 2, 1138–1143 (2001).
Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).
Bennett, S. R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).
Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).
Kaech, S. M. & Ahmed, R. Memory CD8+ T-cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunol. 2, 415–422 (2001).
Wong, P. & Pamer, E. G. Cutting edge: antigen-independent CD8 T-cell proliferation. J. Immunol. 166, 5864–5868 (2001).
Van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nature Immunol. 2, 423–429 (2001).
Foulds, K. E. et al. Cutting edge: CD4 and CD8 T cells are intrinsically different in their proliferative responses. J. Immunol. 168, 1528–1532 (2002).
Roman, E. et al. CD4 effector T-cell subsets in the response to influenza: heterogeneity, migration and function. J. Exp. Med. 196, 957–968 (2002).
Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).
Lauvau, G. et al. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 294, 1735–1739 (2001).
Wu, C. Y. et al. Distinct lineages of TH1 cells have differential capacities for memory-cell generation in vivo. Nature Immunol. 3, 852–858 (2002).
Oehen, S. & Brduscha-Riem, K. Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J. Immunol. 161, 5338–5346 (1998).
Opferman, J. T., Ober, B. T. & Ashton-Rickardt, P. G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).
Weninger, W., Crowley, M. A., Manjunath, N. & von Andrian, U. H. Migratory properties of naive, effector and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).
Hou, S., Hyland, L., Ryan, K. W., Portner, A. & Doherty, P. C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652–654 (1994).
Fernando, G. J., Khammanivong, V., Leggatt, G. R., Liu, W. J. & Frazer, I. H. The number of long-lasting functional memory CD8+ T cells generated depends on the nature of the initial nonspecific stimulation. Eur. J. Immunol. 32, 1541–1549 (2002).
Smith, K. A. Interleukin-2: inception, impact and implications. Science 240, 1169–1176 (1988).
Janeway, C. A. Jr & Bottomly, K. Signals and signs for lymphocyte responses. Cell 76, 275–285 (1994).
Schluns, K. S., Williams, K., Ma, A., Zheng, X. X. & Lefrançois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002). This study, together with references 55 and 77, shows that IL-15 and IL-15Rα are required for the basal proliferation of antigen-specific memory CD8+ T cells in immunocompetent mice.
Vella, A. T., Teague, T. K., Ihle, J. N., Kappler, J. & Marrack, P. Interleukin-4 (IL-4) or IL-7 prevents the death of resting T cells: STAT6 is probably not required for the effect of IL-4. J. Exp. Med. 186, 325–330 (1997).
Vella, A. T., Dow, S., Potter, T. A., Kappler, J. & Marrack, P. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc. Natl Acad. Sci. USA 95, 3810–3815 (1998).
Grabstein, K. H. et al. Regulation of T-cell proliferation by IL-7. J. Immunol. 144, 3015–3020 (1990).
Rathmell, J. C., Farkash, E. A., Gao, W. & Thompson, C. B. IL-7 enhances the survival and maintains the size of naive T cells. J. Immunol. 167, 6869–6876 (2001).
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000). The first demonstration that IL-7 is required for homeostatic proliferation of CD4+ and CD8+ T cells after transfer into a lymphopenic host. This study showed that IL-7Rα is expressed by naive and memory T cells and that the generation of antigen-specific memory CD8+ T cells is defective in the absence of IL-7Rα expression.
Zhang, X., Sun, S., Hwang, I., Tough, D. F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cell in vivo by IL-15. Immunity 8, 591–599 (1998). The first demonstration that memory-phenotype CD8+ T cells have increased levels of expression of the IL-2R β-chain, which correlates with an increased responsiveness to IL-15.
D'Souza, W. N., Schluns, K. S., Masopust, D. & Lefrançois, L. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T-cell responses. J. Immunol. 168, 5566–5572 (2002).
Khoruts, A., Mondino, A., Pape, K. A., Reiner, S. L. & Jenkins, M. K. A natural immunological adjuvant enhances T-cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J. Exp. Med. 187, 225–236 (1998).
Cousens, L. P., Orange, J. S. & Biron, C. A. Endogenous IL-2 contributes to T-cell expansion and IFN-γ production during lymphocytic choriomeningitis virus production. J. Immunol. 155, 5690–5699 (1995).
Utermohlen, O., Tarnok, A., Bonig, L. & Lehmann-Grube, F. T-lymphocyte-mediated antiviral immune responses in mice are diminished by treatment with monoclonal antibody directed against the interleukin-2 receptor. Eur. J. Immunol. 24, 3093–3099 (1994).
Kundig, T. M. et al. Immune responses in interleukin-2-deficient mice. Science 262, 1059–1061 (1993).
Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).
Kneitz, B., Herrmann, T., Yonehara, S. & Schimpl, A. Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur. J. Immunol. 25, 2572–2577 (1995).
Leung, D. T., Morefield, S. & Willerford, D. M. Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo. J. Immunol. 164, 3527–3534 (2000).
Lantz, O., Grandjean, I., Matzinger, P. & Di Santo, J. P. γ-chain required for naive CD4+ T-cell survival but not for antigen proliferation. Nature Immunol. 1, 54–58 (2000).
Grabstein, K. H. et al. Cloning of a T-cell growth factor that interacts with the β-chain of the interleukin-2 receptor. Science 264, 965–968 (1994).
Flamand, L., Stefanescu, I. & Menezes, J. Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15. J. Clin. Invest. 97, 1373–1381 (1996).
Carson, W. E. et al. Endogenous production of interleukin-15 by activated human monocytes is critical for optimal production of interferon-γ by natural killer cells in vitro. J. Clin. Invest. 96, 2578–2582 (1995).
Atedzoe, B. N., Ahmad, A. & Menezes, J. Enhancement of natural killer cell cytotoxicity by the human herpesvirus-7 via IL-15 induction. J. Immunol. 159, 4966–4972 (1997).
Doherty, T. M., Seder, R. A. & Sher, A. Induction and regulation of IL-15 expression in murine macrophages. J. Immunol. 156, 735–741 (1996).
Mody, C. H., Spurrell, J. C. & Wood, C. J. Interleukin-15 induces antimicrobial activity after release by Cryptococcus neoformans-stimulated monocytes. J. Infect. Dis. 178, 803–814 (1998).
Nishimura, H. et al. IL-15 is a novel growth factor for murine γδ T cells induced by Salmonella infection. J. Immunol. 156, 663–669 (1996).
Becker, T. C. et al. Interleukin-15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).
Badovinac, V. P., Porter, B. B. & Harty, J. T. Programmed contraction of CD8+ T cells after infection. Nature Immunol. 3, 619–626 (2002).
Badovinac, V. P., Tvinnereim, A. R. & Harty, J. T. Regulation of antigen-specific CD8+ T-cell homeostasis by perforin and interferon-γ. Science 290, 1354–1358 (2000).
Dalton, D. K., Haynes, L., Chu, C. Q., Swain, S. L. & Wittmer, S. Interferon-γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J. Exp. Med. 192, 117–122 (2000).
Refaeli, Y., Van Parijs, L., London, C. A., Tschopp, J. & Abbas, A. K. Biochemical mechanisms of IL-2-regulated Fas-mediated T-cell apoptosis. Immunity 8, 615–623 (1998).
Yajima, T. et al. Overexpression of IL-15 in vivo increases antigen-driven memory CD8+ T cells following a microbe exposure. J. Immunol. 168, 1198–1203 (2002).
Maraskovsky, E. et al. Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells. J. Immunol. 157, 5315–5323 (1996).
Hassan, J. & Reen, D. J. IL-7 promotes the survival and maturation, but not differentiation of human post-thymic CD4+ T cells. Eur. J. Immunol. 28, 3057–3065 (1998).
Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R. & Weissman, I. L. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89, 1033–1041 (1997).
Maraskovsky, E. et al. Bcl-2 can rescue T-lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant Rag1−/− mice. Cell 89, 1011–1019 (1997).
Kim, K., Lee, C. K., Sayers, T. J., Muegge, K. & Durum, S. K. The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2 and T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J. Immunol. 160, 5735–5741 (1998).
Schober, S. L. et al. Expression of the transcription factor lung Kruppel-like factor is regulated by cytokines and correlates with survival of memory T cells in vitro and in vivo. J. Immunol. 163, 3662–3667 (1999).
Tough, D. F. & Sprent, J. Turnover of naive- and memory-phenotype T cells. J. Exp. Med. 179, 1127–1135 (1994).
Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).
Tough, D. F. & Sprent, J. Lifespan of lymphocytes. Immunol. Res. 14, 1–12 (1995).
Bruno, L., von Boehmer, H. & Kirberg, J. Cell division in the compartment of naive and memory T lymphocytes. Eur. J. Immunol. 26, 3179–3184 (1996).
Murali-Krishna, K. et al. Persistence of memory CD8 T cells in MHC class-I-deficient mice. Science 286, 1377–1381 (1999).
Swain, S. L., Hu, H. & Huston, G. Class-II-independent generation of CD4 memory T cells from effectors. Science 286, 1381–1383 (1999).
Kassiotis, G., Garcia, S., Simpson, E. & Stockinger, B. Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nature Immunol. 3, 244–250 (2002).
Kanai, T., Thomas, E. K., Yasutomi, Y. & Letvin, N. L. IL-15 stimulates the expansion of AIDS virus-specific CTL. J. Immunol. 157, 3681–3687 (1996).
Kanegane, H. & Tosato, G. Activation of naive and memory T cells by interleukin-15. Blood 88, 230–235 (1996).
Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000). This study shows that IL-2 and IL-15 have contrasting roles in memory CD8+ T-cell proliferation, and that in vivo treatment with IL-2/IL-15Rβ-specific antibodies causes a decrease in the proliferation of memory-phenotype CD8+ T cells, whereas blocking IL-2 causes an increase in memory CD8+ T-cell proliferation.
Goldrath, A. W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).
Kieper, W. C. et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Masopust, D., Vezys, V., Marzo, A. L. & Lefrançois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).
Masopust, D., Jiang, J., Shen, H. & Lefrançois, L. Direct analysis of the dynamics of the intestinal mucosa CD8 T-cell response to systemic virus infection. J. Immunol. 166, 2348–2356 (2001).
Choi, E. Y. et al. Quantitative analysis of the immune response to mouse non-MHC transplantation antigens in vivo: the H60 histocompatibility antigen dominates over all others. J. Immunol. 166, 4370–4379 (2001).
Grayson, J. M., Harrington, L. E., Lanier, J. G., Wherry, E. J. & Ahmed, R. Differential sensitivity of naive and memory CD8+ T cells to apoptosis in vivo. J. Immunol. 169, 3760–3770 (2002).
Tough, D. F., Borrow, P. & Sprent, J. Induction of bystander T-cell proliferation by viruses and type I interferon in vivo. Science 272, 1947–1950 (1996).
Tough, D. F., Sun, S. & Sprent, J. T-cell stimulation in vivo by lipopolysaccharide (LPS). J. Exp. Med. 185, 2089–2094 (1997).
Lodolce, J. P., Burkett, P. R., Boone, D. L., Chien, M. & Ma, A. T-cell-independent interleukin-15Rα signals are required for bystander proliferation. J. Exp. Med. 194, 1187–1194 (2001). Whereas most studies have examined direct effects of IL-15 on T cells, this study showed that IL-15 can mediate bystander proliferation of CD8+ T cells through mechanisms that do not require expression of IL-15Rα by T cells, but instead by non-T cells.
Judge, A. D., Zhang, X., Fujii, H., Surh, C. D. & Sprent, J. Interleukin-15 controls both proliferation and survival of a subset of memory-phenotype CD8+ T cells. J. Exp. Med. 196, 935–946 (2002).
Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).
Andreasen, S. O., Christensen, J. P., Marker, O. & Thomsen, A. R. Virus-induced non-specific signals cause cell-cycle progression of primed CD8+ T cells, but do not induce cell differentiation. Int. Immunol. 11, 1463–1473 (1999).
Hodes, R. J. Aging and the immune system. Immunol. Rev. 160, 5–8 (1997).
Miller, R. A., Garcia, G., Kirk, C. J. & Witkowski, J. M. Early activation defects in T lymphocytes from aged mice. Immunol. Rev. 160, 79–90 (1997).
Linton, P. J., Haynes, L., Tsui, L., Zhang, X. & Swain, S. From naive to effector — alterations with aging. Immunol. Rev. 160, 9–18 (1997).
Zhang, X. et al. Aging leads to disturbed homeostasis of memory phenotype CD8+ cells. J. Exp. Med. 195, 283–293 (2002).
Freitas, A. A. & Rocha, B. Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83–111 (2000).
Selin, L. K. et al. Attrition of T-cell memory: selective loss of LCMV epitope-specific memory CD8 T cells following infections with heterologous viruses. Immunity 11, 733–742 (1999).
Varga, S. M., Selin, L. K. & Welsh, R. M. Independent regulation of lymphocytic choriomeningitis virus-specific T-cell memory pools: relative stability of CD4 memory under conditions of CD8 memory T-cell loss. J. Immunol. 166, 1554–1561 (2001).
Homann, D., Teyton, L. & Oldstone, M. B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nature Med. 7, 913–919 (2001).
Giri, J. G. et al. Utilization of the β and γ chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822–2830 (1994).
Waldmann, T. A., Dubois, S. & Tagaya, Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14, 105–110 (2001).
Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858–861 (1991).
Zheng, L., Trageser, C. L., Willerford, D. M. & Lenardo, M. J. T-cell growth cytokines cause the superinduction of molecules mediating antigen-induced T-lymphocyte death. J. Immunol. 160, 763–769 (1998).
Dai, Z., Arakelov, A., Wagener, M., Konieczny, B. T. & Lakkis, F. G. The role of the common cytokine receptor γ-chain in regulating IL-2-dependent, activation-induced CD8+ T-cell death. J. Immunol. 163, 3131–3137 (1999).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Murakami, M., Sakamoto, A., Bender, J., Kappler, J. & Marrack, P. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc. Natl Acad. Sci. USA 99, 8832–8837 (2002).
Furtado, G. C., De Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin-2 signaling is required for CD4+ regulatory T-cell function. J. Exp. Med. 196, 851–857 (2002).
Anderson, D. M. et al. Functional characterization of the human interleukin-15 receptor α-chain and close linkage of IL15RA and IL2RA genes. J. Biol. Chem. 270, 29862–29869 (1995).
Dubois, S., Mariner, J., Waldmann, T. A. & Tagaya, Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547 (2002). A surprising demonstration that IL-15Rα recycles and can present IL-15 to opposing cells expressing the IL-2/IL-15Rβ and common γ-chain subunits, but not IL-15Rα.
Marks-Konczalik, J. et al. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc. Natl Acad. Sci. USA 97, 11445–11450 (2000).
Ruchatz, H., Leung, B. P., Wei, X. Q., McInnes, I. B. & Liew, F. Y. Soluble IL-15 receptor α-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J. Immunol. 160, 5654–5660 (1998).
Saint-Vis, B. et al. The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation. J. Immunol. 160, 1666–1667 (1998).
Bamford, R. N., Battiata, A. P., Burton, J. D., Sharma, H. & Waldmann, T. A. Interleukin (IL)-15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation. Proc. Natl Acad. Sci. USA 93, 2897–2902 (1996).
Tagaya, Y. et al. Generation of secretable and nonsecretable interleukin-15 isoforms through alternate usage of signal peptides. Proc. Natl Acad. Sci. USA 94, 14444–14449 (1997).
Giri, J. G. et al. Identification and cloning of a novel IL-15-binding protein that is structurally related to the α-chain of the IL-2 receptor. EMBO J. 14, 3654–3663 (1995).
Dubois, S. et al. Natural splicing of exon 2 of human interleukin-15 receptor α-chain mRNA results in a shortened form with a distinct pattern of expression. J. Biol. Chem. 274, 26978–26984 (1999).
Tagaya, Y., Burton, J. D., Miyamoto, Y. & Waldmann, T. A. Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. EMBO J. 15, 4928–4939 (1996).
Tagaya, Y., Bamford, R. N., DeFilippis, A. P. & Waldmann, T. A. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4, 329–336 (1996).
Masuda, A. et al. Interleukin-15 induces rapid tyrosine phosphorylation of STAT6 and the expression of interleukin-4 in mouse mast cells. J. Biol. Chem. 275, 29331–29337 (2000).
Greene, W. C. et al. Stable expression of cDNA encoding the human interleukin-2 receptor in eukaryotic cells. J. Exp. Med. 162, 363–368 (1985).
Johnston, J. A., Bacon, C. M., Riedy, M. C. & O'Shea, J. J. Signaling by IL-2 and related cytokines: JAKs, STATs and relationship to immunodeficiency. J. Leukocyte Biol. 60, 441–452 (1996).
Tan, J. T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory-phenotype CD8+ cells but are not required for memory-phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).
Acknowledgements
Work in our laboratory is supported by grants from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Glossary
- COMMON CYTOKINE RECEPTOR γ-CHAIN FAMILY
-
A family of cytokine receptors in which each receptor complex is composed of two or three subunits, with one of those subunits being the common cytokine receptor γ-chain (γc).
- MHC CLASS I TETRAMERS
-
Biotinylated monomeric MHC molecules are folded with a specific peptide in the binding groove and tetramerized with a fluorescently labelled streptavidin molecule. Tetramers will bind to T cells that express T-cell receptors specific for the cognate peptide.
- TOLL-LIKE RECEPTORS
-
(TLRs). A family of receptors that recognize conserved products unique to microorganisms (such as lipopolysaccharide). Stimulation through TLRs induces dendritic-cell maturation and activation, leading to optimal activation of the adaptive immune response. TLR-mediated events signal to the host that a microbial pathogen is present.
- NON-LYMPHOID TISSUES
-
Any tissue that is not considered to be a primary or secondary lymphoid organ. Non-lymphoid tissues, such as lung, liver and intestine, harbour as many activated and memory T cells as do the secondary lymphoid tissues.
- BCL-2-FAMILY MEMBERS
-
Mitochondrial proteins that increase or decrease the susceptibility of a cell to apoptosis. When levels of either BCL-2 or BCL-XL are increased, a cell is more resistant to cell death.
- CD44
-
A cell-surface glycoprotein that is expressed by many cell types. Among CD8+ T cells, expression of CD44 is upregulated after activation and remains at high levels on memory T cells.
- BROMODEOXYURIDINE
-
(BrdU). A thymidine analogue that is incorporated into DNA during DNA replication. In vivo or in vitro treatment with BrdU can allow the detection of dividing cells by intracellular staining with fluorescence-labelled BrdU-specific antibodies followed by flow cytometry.
- 5,6-CARBOXYFLUORESCEIN DIACETATE SUCCINIMIDYL ESTER
-
(CFSE). An intravital fluorescent dye that is equally distributed between daughter cells after each cell division, thereby allowing the division history of a cell to be determined (up to ∼8 divisions) by flow cytometry.
- CD62L
-
Also known as L-selectin, this molecule binds to peripheral-node addressin on high endothelial venules and acts as a homing receptor allowing T cells to traffic to lymph nodes.
- INTRACELLULAR CYTOKINE STAINING
-
An assay used to identify cells that produce cytokines in response to activation signals. Activated or memory T cells will produce cytokines after brief in vitro stimulation with antigen. While in culture, the secretion of these cytokines is blocked, allowing a sufficient quantity to build up intracellularly to allow detection using fluorescence-labelled cytokine-specific antibodies and flow cytometry.
Rights and permissions
About this article
Cite this article
Schluns, K., Lefrançois, L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3, 269–279 (2003). https://doi.org/10.1038/nri1052
Issue Date:
DOI: https://doi.org/10.1038/nri1052
This article is cited by
-
Optimizing the manufacturing and antitumour response of CAR T therapy
Nature Reviews Bioengineering (2023)
-
Pasteurization of human milk affects the miRNA cargo of EVs decreasing its immunomodulatory activity
Scientific Reports (2023)
-
Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging
Immunity & Ageing (2022)
-
Effect of IL-15 addition on asbestos-induced suppression of human cytotoxic T lymphocyte induction
Environmental Health and Preventive Medicine (2021)
-
Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses
Nature Cell Biology (2021)