Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Concomitant regulation of T-cell activation and homeostasis

Nature Reviews Immunology volume 4, pages 387–395 (2004)Cite this article

Abstract

T cells constitute a heterogeneous, hierarchically organized population, comprising several maturation/differentiation states that have different capacities for clonal expansion and self-renewal. Here, we argue that the relative probabilities of proliferation, differentiation and death — the cellular events that determine the population's structure, as well as its size — are not entirely pre-programmed or fixed; instead, these events are regulated dynamically through the recurrent interaction of lymphocytes with exogenous and endogenous antigens, antigen-presenting cells and each other.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Homeostasis implies replacement of activated memory cells by the progeny of naive cells.
Figure 2: Feedback regulated 'balance of growth' for activated T cells.
Figure 3: Hypothetical chronology of clonal expansion and differentiation.

Similar content being viewed by others

References

  1. Marrack, P. et al. Homeostasis of αβ-TCR+ T cells. Nature Immunol. 1, 107–111 (2000).

    Article  CAS  Google Scholar 

  2. Tanchot, C. & Rocha, B. The organization of mature T-cell pools. Immunol. Today 19, 575–579 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Freitas, A. A. & Rocha, B. Peripheral T cell survival. Curr. Opin. Immunol. 11, 152–156 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Freitas, A. A. & Rocha, B. Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Flynn, K. J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Blattman, J. N. et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J. Exp. Med. 195, 657–664 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jenkins, M. K. et al. In vivo activation of antigen-specific CD4 T cells. Annu. Rev. Immunol. 19, 23–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Brenchley, J. M. et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101, 2711–2720 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Opferman, J. T., Ober, B. T. & Ashton-Rickardt, P. G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nature Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  16. van Lier, R. A., ten Berge, I. J. & Gamadia, L. E. Human CD8+ T-cell differentiation in response to viruses. Nature Rev. Immunol. 3, 931–939 (2003).

    Article  CAS  Google Scholar 

  17. Hayashi, N., Liu, D., Min, B., Ben-Sasson, S. Z. & Paul, W. E. Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells. Proc. Natl Acad. Sci. USA 99, 6187–6191 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ben-Sasson, S. Z. et al. Generation and characterization of memory CD4 T cells. Adv. Exp. Med. Biol. 512, 129–134 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Richter, A., Lohning, M. & Radbruch, A. Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J. Exp. Med. 190, 1439–1450 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Laouar, Y. & Crispe, I. N. Functional flexibility in T cells: independent regulation of CD4+ T cell proliferation and effector function in vivo. Immunity 13, 291–301 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Ben-Sasson, S. Z., Gerstel, R., Hu-Li, J. & Paul, W. E. Cell division is not a 'clock' measuring acquisition of competence to produce IFN-γ or IL-4. J. Immunol. 166, 112–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Auphan-Anezin, N., Verdeil, G. & Schmitt-Verhulst, A. M. Distinct thresholds for CD8 T cell activation lead to functional heterogeneity: CD8 T cell priming can occur independently of cell division. J. Immunol. 170, 2442–2448 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Grossman, Z. Recognition of self, balance of growth and competition: horizontal networks regulate immune responsiveness. Eur. J. Immunol. 12, 747–756 (1982).

    Article  CAS  PubMed  Google Scholar 

  26. Grossman, Z. The stem cell concept revisited: self-renewal capacity is a dynamic property of hemopoietic cells. Leuk. Res. 10, 937–950 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Grossman, Z. Cellular tolerance as a dynamic state of the adaptable lymphocyte. Immunol. Rev. 133, 45–73 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Lanzavecchia, A., Lezzi, G. & Viola, A. From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96, 1–4 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Langenkamp, A., Messi, M., Lanzavecchia, A. & Sallusto, F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nature Immunol. 1, 311–316 (2000).

    Article  CAS  Google Scholar 

  31. Wang, X. & Mosmann, T. In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-γ, and can subsequently differentiate into IL-4- or IFN-γ-secreting cells. J. Exp. Med. 194, 1069–1080 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nature Immunol. 1, 47–53 (2000).

    Article  CAS  Google Scholar 

  33. Morrison, S. J., Uchida, N. & Weissman, I. L. The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 11, 35–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Badovinac, V. P., Porter, B. B. & Harty, J. T. Programmed contraction of CD8+ T cells after infection. Nature Immunol. 3, 619–626 (2002).

    Article  CAS  Google Scholar 

  36. Blattman, J. N., Cheng, L. E. & Greenberg, P. D. CD8+ T cell responses: it's all downhill after their prime. Nature Immunol. 3, 601–602 (2002).

    Article  CAS  Google Scholar 

  37. Badovinac, V. P., Messingham, K. A., Hamilton, S. E. & Harty, J. T. Regulation of CD8+ T cells undergoing primary and secondary responses to infection in the same host. J. Immunol. 170, 4933–4942 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Grossman, Z. Recognition of self and regulation of specificity at the level of cell populations. Immunol. Rev. 79, 119–138 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Grossman, Z. & Paul, W. E. Autoreactivity, dynamic tuning and selectivity. Curr. Opin. Immunol. 13, 687–698 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Butz, E. A. & Bevan, M. J. Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8, 167–175 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kedl, R. M. et al. T cells compete for access to antigen-bearing antigen-presenting cells. J. Exp. Med. 192, 1105–1113 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kedl, R. M., Schaefer, B. C., Kappler, J. W. & Marrack, P. T cells down-modulate peptide–MHC complexes on APCs in vivo. Nature Immunol. 3, 27–32 (2002).

    Article  CAS  Google Scholar 

  43. Kedl, R. M., Kappler, J. W. & Marrack, P. Epitope dominance, competition and T cell affinity maturation. Curr. Opin. Immunol. 15, 120–127 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Wong, P. & Pamer, E. G. Feedback regulation of pathogen-specific T cell priming. Immunity 18, 499–511 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Shevach, E. M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).

    Article  CAS  Google Scholar 

  47. 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).

    Article  CAS  Google Scholar 

  48. 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).

    Article  CAS  Google Scholar 

  49. Bird, J. J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Kaech, S. M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Grossman, Z. & Paul, W. E. Self-tolerance: context dependent tuning of T cell antigen recognition. Semin. Immunol. 12, 197–203; discussion 257–344 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Grossman, Z. & Herberman, R. B. T-cell homeostasis in HIV infection is neither failing nor blind: modified cell counts reflect an adaptive response of the host. Nature Med. 3, 486–490 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Grossman, Z. & Paul, W. E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc. Natl Acad. Sci. USA 89, 10365–10369 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tanchot, C., Barber, D. L., Chiodetti, L. & Schwartz, R. H. Adaptive tolerance of CD4+ T cells in vivo: multiple thresholds in response to a constant level of antigen presentation. J. Immunol. 167, 2030–2039 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Bhandoola, A. et al. Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4+ T cells: evidence from a lymphopenic T cell model. Immunity 17, 425–436 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Almeida, A. R., Legrand, N., Papiernik, M. & Freitas, A. A. Homeostasis of peripheral CD4+ T cells: IL-2Rα and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169, 4850–4860 (2002).

    Article  PubMed  Google Scholar 

  57. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002).

    Article  CAS  Google Scholar 

  58. Stockinger, B., Barthlott, T. & Kassiotis, G. T cell regulation: a special job or everyone's responsibility? Nature Immunol. 2, 757–758 (2001).

    Article  CAS  Google Scholar 

  59. Barthlott, T., Kassiotis, G. & Stockinger, B. T cell regulation as a side effect of homeostasis and competition. J. Exp. Med. 197, 451–460 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, X., Sun, S., Hwang, I., Tough, D. F. & Sprent, J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8, 591–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Adorini, L., Penna, G., Giarratana, N. & Uskokovic, M. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J. Cell. Biochem. 88, 227–233 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Qin, S. et al. 'Infectious' transplantation tolerance. Science 259, 974–977 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Harrington, L. E., Galvan, M., Baum, L. G., Altman, J. D. & Ahmed, R. Differentiating between memory and effector CD8 T cells by altered expression of cell surface O-glycans. J. Exp. Med. 191, 1241–1246 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Langenkamp, A. et al. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur. J. Immunol. 33, 474–482 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Turner, S. J., Cross, R., Xie, W. & Doherty, P. C. Concurrent naive and memory CD8+ T cell responses to an influenza A virus. J. Immunol. 167, 2753–2758 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Brander, C. et al. Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection. J. Immunol. 162, 4796–4800 (1999).

    CAS  PubMed  Google Scholar 

  70. Islam, S. A. et al. Persistence of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte clones in a subject with rapid disease progression. J. Virol. 75, 4907–4911 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Douek, D. C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Kong, F. K., Chen, C. L., Six, A., Hockett, R. D. & Cooper, M. D. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl Acad. Sci. USA 96, 1536–1540 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Poulin, J. F. et al. Direct evidence for thymic function in adult humans. J. Exp. Med. 190, 479–486 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hazenberg, M. D. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nature Med. 6, 1036–1042 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Douek, D. C. et al. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J. Immunol. 167, 6663–6668 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Grossman, Z. & Singer, A. Tuning of activation thresholds explains flexibility in the selection and development of T cells in the thymus. Proc. Natl Acad. Sci. USA 93, 14747–14752 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Jameson, S. C. Maintaining the norm: T-cell homeostasis. Nature Rev. Immunol. 2, 547–556 (2002).

    Article  CAS  Google Scholar 

  79. Min, B. et al. Neonates support lymphopenia-induced proliferation. Immunity 18, 131–140 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Kieper, W. C. & Jameson, S. C. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide–MHC ligands. Proc. Natl Acad. Sci. USA 96, 13306–13311 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ge, Q., Rao, V. P., Cho, B. K., Eisen, H. N. & Chen, J. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide–MHC epitopes and strength of their interaction with T cell receptors. Proc. Natl Acad. Sci. USA 98, 1728–1733 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kassiotis, G., Zamoyska, R. & Stockinger, B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J. Exp. Med. 197, 1007–1016 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Min, B., Foucras, G., Meier-Schellersheim, M. & Paul, W. E. Spontaneous proliferation, a response of naïve CD4 T cells determined by the diversity of the memory cell repertoire. Proc. Natl Acad. Sci. USA 101, 3874–3879 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Moses, C. T., Thorstenson, K. M., Jameson, S. C. & Khoruts, A. Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells. Proc. Natl Acad. Sci. USA 100, 1185–1190 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Troy, A. E. & Shen, H. Cutting edge: homeostatic proliferation of peripheral T lymphocytes is regulated by clonal competition. J. Immunol. 170, 672–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Tanchot, C. et al. Conversion of naive T cells to a memory-like phenotype in lymphopenic hosts is not related to a homeostatic mechanism that fills the peripheral naive T cell pool. J. Immunol. 168, 5042–5046 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Ge, Q., Hu, H., Eisen, H. N. & Chen, J. Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. Proc. Natl Acad. Sci. USA 99, 2989–2994 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Kimmig, S. et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Berzins, S. P., Boyd, R. L. & Miller, J. F. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839–1848 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Berzins, S. P., Godfrey, D. I., Miller, J. F. & Boyd, R. L. A central role for thymic emigrants in peripheral T cell homeostasis. Proc. Natl Acad. Sci. USA 96, 9787–9791 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Di Rosa, F., Ramaswamy, S., Ridge, J. P. & Matzinger, P. On the lifespan of virgin T lymphocytes. J. Immunol. 163, 1253–1257 (1999).

    CAS  PubMed  Google Scholar 

  93. Goronzy, J. J. & Weyand, C. M. Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol. 22, 251–255 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Seder, R. A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nature Immunol. 4, 835–842 (2003).

    Article  CAS  Google Scholar 

  95. Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shedlock, D. J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Bray, D. Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Germain, R. N. & Stefanova, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nature Immunol. 4, 248–254 (2003).

    Article  CAS  Google Scholar 

  100. Mueller, D. L. Tuning the immune system: competing positive and negative feedback loops. Nature Immunol. 4, 210–211 (2003).

    Article  CAS  Google Scholar 

  101. Bitmansour, A. D., Douek, D. C., Maino, V. C. & Picker, L. J. Direct ex vivo analysis of human CD4+ memory T cell activation requirements at the single clonotype level. J. Immunol. 169, 1207–1218 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Azzam, H. S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Smith, K. et al. Sensory adaptation in naive peripheral CD4 T cells. J. Exp. Med. 194, 1253–1261 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bitegye, C., Hannier, S., Guerif, S., Valitutti, S. & Demotz, S. Tuning of T cell clone size and activation threshold by control of CD25 expression through mitogen-activated protein kinase pathways. Int. Arch. Allergy Immunol. 127, 322–332 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Stamou, P. et al. Chronic exposure to low levels of antigen in the periphery causes reversible functional impairment correlating with changes in CD5 levels in monoclonal CD8 T cells. J. Immunol. 171, 1278–1284 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Anderton, S. M. & Wraith, D. C. Selection and fine-tuning of the autoimmune T-cell repertoire. Nature Rev. Immunol. 2, 487–498 (2002).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Zvi Grossman

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethedsa, 20892, Maryland, USA

    Zvi Grossman

  3. the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Booki Min, Martin Meier-Schellersheim & William E. Paul

Authors
  1. Zvi Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Booki Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Meier-Schellersheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William E. Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zvi Grossman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

LocusLink

BCL-2

CCR7

CD4

CD8

CD27

CD28

CD31

CD45

CD57

CD62L

IFN-γ

IL-2

IL-4

IL-7

IL-12

FURTHER INFORMATION

William Paul's lab

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grossman, Z., Min, B., Meier-Schellersheim, M. et al. Concomitant regulation of T-cell activation and homeostasis. Nat Rev Immunol 4, 387–395 (2004). https://doi.org/10.1038/nri1355

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1355

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing