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  • Review Article
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Helping the CD8+ T-cell response

Nature Reviews Immunology volume 4, pages 595–602 (2004)Cite this article

Key Points

  • Strong cytotoxic T lymphocyte (CTL) responses to cellular antigen that does not provide its own endogenous inflammatory signals require CD4+ T cells to recognize antigen.

  • The role of CD4+ T cells is to activate or 'license' the ability of dendritic cells (DCs) to present antigen, so that a strong CD8+ T-cell response can ensue.

  • When antigen is in the form of a pathogen, the need for CD4+ T-cell recognition of antigen may be overridden, as the DC can be activated directly by pathogen-associated molecular patterns.

  • When CD8+ T-cell responses are induced in a CD4+ T-cell-deficient environment, even though a good primary response occurs, the ability to make a good secondary response fades.

  • This finding has been interpreted either as a requirement for CD4+ T cells to programme CD8+ T cells for long-term memory differentiation, or for CD4+ T cells to provide factors that maintain CD8+ memory T cells.

  • When antigen persists in an animal, memory CD8+ T-cell differentiation cannot occur. Depending on the level of persistent antigen, the CD8+ T cells might be rapidly or slowly eliminated. Whether CD4+ T cells can directly promote CD8+ T-cell survival in the presence of persisting antigen is unclear.

Abstract

Cytotoxic T lymphocytes (CTLs) that express the CD8 co-receptor are the guided missiles of the immune system. They express clonally distributed receptors for foreign antigen, undergo marked proliferation in response to infection and kill any cell that expresses their target antigen. When an infection is cleared or brought under control, the progeny of these cytolytic effectors are retained as an essential component of immunological memory. As I discuss here, similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.

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Figure 1: The classical understanding of how CD4+ T cells are required for certain cytotoxic T lymphocyte (CTL) responses but not for others.
Figure 2: Recent reports have indicated that although the primary cytotoxic T lymphocyte (CTL) response is independent of CD4+ T-cell help, all secondary responses require CD4+ T-cell help.
Figure 3: There are two phases of the response to acute antigen exposure, the first when antigen is present and the second when antigen has been cleared.

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References

  1. Murali-Krishna, K. et al. Counting antigen-specific CD8+ T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Doherty, P. C. The numbers game for virus-specific CD8+ T cells. Science 280, 227 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Callan, M. F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein–Barr virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Melief, C. J. Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur. J. Immunol. 33, 2645–2654 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Wilson, D. B. & Blyth, J. N. P. Quantitative studies on the mixed lymphocyte interaction in rats. Kinetics of the response. J. Exp. Med. 128, 1157–1181 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lindahl, K. F. & Bach, F. H. Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction. J. Exp. Med. 144, 305–318 (1976).

    Article  CAS  PubMed  Google Scholar 

  8. Keene, J. A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cassell, D. & Forman, J. Linked recognition of helper and cytotoxic antigenic determinants for the generation of cytotoxic T lymphocytes. Ann. NY Acad. Sci. 532, 51–60 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Husmann, L. A. & Bevan, M. J. Cooperation between helper T cells and cytotoxic T lymphocyte precursors. Ann. NY Acad. Sci. 532, 158–169 (1988).

    Article  CAS  PubMed  Google Scholar 

  11. Guerder, S. & Matzinger, P. A fail-safe mechanism for maintaining self-tolerance. J. Exp. Med. 176, 553–564 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Mitchison, N. A. & O'Malley, C. Three-cell-type clusters of T cells with antigen-presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response. Eur. J. Immunol. 17, 1579–1583 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. Bennett, S. R., Carbone, F. R., Karamalis, F., Miller, J. F. & Heath, W. R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J. Exp. Med. 186, 65–70 (1997). A study showing that MHC class-II-restricted T cells must recognize antigen on the same DC that presents antigen to MHC class-I-restricted T cells to stimulate an effective CTL response against ovalbumin-loaded cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Bennett, S. R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. 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). Together with references 14 and 15, this work shows that DCs can be activated by ligation of CD40 to enable them to become potent stimulators of a primary CD8+ T-cell response, even in the absence of CD4+ T-cell help.

    Article  CAS  PubMed  Google Scholar 

  17. Curtsinger, J. M., Lins, D. C. & Mescher, M. F. Signal 3 determines tolerance versus full activation of naive CD8+ T cells: dissociating proliferation and development of effector function. J. Exp. Med. 197, 1141–1151 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hernandez, J., Aung, S., Marquardt, K. & Sherman, L. A. Uncoupling of proliferative potential and gain of effector function by CD8+ T cells responding to self-antigens. J. Exp. Med. 196, 323–333 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buller, R. M., Holmes, K. L., Hugin, A., Frederickson, T. N. & Morse, H. C. Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77–79 (1987).

    Article  CAS  PubMed  Google Scholar 

  20. Rahemtulla, A. et al. Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353, 180–184 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Wu, Y. & Liu, Y. Viral induction of co-stimulatory activity on antigen-presenting cells bypasses the need for CD4+ T-cell help in CD8+ T-cell responses. Curr. Biol. 4, 499–505 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Bourgeois, C., Rocha, B. & Tanchot, C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297, 2060–2063 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003). This paper presents the surprising result that, after immunization with tumour cells and using intracellular cytokine staining to quantitate the response, the primary effector response is independent of CD4+ T-cell help, but in the absence of help, no CD8+ T-cell memory is generated.

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Sun, J. C. & Bevan, M. J. Defective CD8+ T cell memory following acute infection without CD4+ T cell help. Science 300, 339–342 (2003). Together with reference 25, these papers show that the primary CTL response to vaccinia virus or Listeria monocytogenes is the same in CD4-sufficient and CD4-deficient mice, whereas protective memory mediated by CD8+ T cells gradually fades in the help-deficient environment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mercado, R. et al. Early programming of T cell populations responding to bacterial infection. J. Immunol. 165, 6833–369 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. 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 

  29. 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 

  30. van Stipdonk, M. J. et al. Dynamic programming of CD8+ T lymphocyte responses. Nature Immunol. 4, 361–365 (2003).

    Article  CAS  Google Scholar 

  31. 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 

  32. Matloubian, M., Concepcion, R. J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056–8063 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. von Herrath, M. G., Yokoyama, M., Dockter, J., Oldstone, M. B. & Whitton, J. L. CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J. Virol. 70, 1072–1079 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Borrow, P. et al. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J. Exp. Med. 183, 2129–2142 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Belz, G. T., Wodarz, D., Diaz, G., Nowak, M. A. & Doherty, P. C. Compromised influenza virus-specific CD8+ T-cell memory in CD4+ T-cell-deficient mice. J. Virol. 76, 12388–12393 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Khanolkar, A., Fuller, M. J. & Zajac, A. J. CD4+ T cell-dependent CD8+ T cell maturation. J. Immunol. 172, 2834–2844 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Masopust, D., Kaech, S. M., Wherry, E. J. & Ahmed, R. The role of programming in memory T-cell development. Curr. Opin. Immunol. 16, 217–225 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, J. C. & Livingstone, A. M. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J. Immunol. 171, 6339–6343 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Sun, J. C. & Bevan, M. J. Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J. Immunol. 172, 3385–3389 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Le Bon, A. et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nature Immunol. 4, 1009–1015 (2003).

    Article  CAS  Google Scholar 

  41. Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Murali-Krishna, K. & Ahmed, R. Cutting edge: naive T cells masquerading as memory cells. J. Immunol. 165, 1733–1737 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Oehen, S. & Brduscha-Riem, K. Naive cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies? Eur. J. Immunol. 29, 608–614 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Cho, B. K., Rao, V. P., Ge, Q., Eisen, H. N. & Chen, J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J. Exp. Med. 192, 549–556 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ruedl, C., Kopf, M. & Bachmann, M. F. CD8+ T cells mediate CD40-independent maturation of dendritic cells in vivo. J. Exp. Med. 189, 1875–1884 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, B. et al. Multiple paths for activation of naive CD8+ T cells: CD4-independent help. J. Immunol. 167, 1283–1289 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Mintern, J. D., Davey, G. M., Belz, G. T., Carbone, F. R. & Heath, W. R. Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells. J. Immunol. 168, 977–980 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Bourgeois, C., Veiga-Fernandes, H., Joret, A. M., Rocha, B. & Tanchot, C. CD8 lethargy in the absence of CD4 help. Eur. J. Immunol. 32, 2199–2207 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Tanchot, C. & Rocha, B. CD8 and B cell memory: same strategy, same signals. Nature Immunol. 4, 431–432 (2003).

    Article  CAS  Google Scholar 

  50. Lee, B. O., Hartson, L. & Randall, T. D. CD40-deficient, influenza-specific CD8 memory T cells develop and function normally in a CD40-sufficient environment. J. Exp. Med. 198, 1759–1764 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8+ T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  52. Huster, K. M. et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl Acad. Sci. USA 101, 5610–5615 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Schluns, K. S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nature Rev. Immunol. 3, 269–279 (2003).

    Article  CAS  Google Scholar 

  59. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000).

    Article  CAS  Google Scholar 

  60. 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 

  61. Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8+ T cell subsets. Nature Immunol. 4, 225–234 (2003). This paper shows that when antigen is cleared there is a progressive differentiation of effector cells to effector memory cells to central memory cells. The latter seem to be most effective in protecting against a pathogen rechallenge.

    Article  CAS  Google Scholar 

  62. Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nature Med. 8, 379–385 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Welsh, R. M. Assessing CD8 T cell number and dysfunction in the presence of antigen. J. Exp. Med. 193, F19–F22 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gallimore, A. et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I–peptide complexes. J. Exp. Med. 187, 1383–1393 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Andreasen, S. O., Christensen, J. E., Marker, O. & Thomsen, A. R. Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses. J. Immunol. 164, 3689–3697 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Thomsen, A. R., Nansen, A., Christensen, J. P., Andreasen, S. O. & Marker, O. CD40 ligand is pivotal to efficient control of virus replication in mice infected with lymphocytic choriomeningitis virus. J. Immunol. 161, 4583–4590 (1998).

    CAS  PubMed  Google Scholar 

  69. Battegay, M. et al. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J. Virol. 68, 4700–4704 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Bachmann, M. F., Hunziker, L., Zinkernagel, R. M., Storni, T. & Kopf, M. Maintenance of memory CTL responses by T helper cells and CD40–CD40 ligand: antibodies provide the key. Eur. J. Immunol. 34, 317–326 (2004). This paper shows that some of the negative effects on CD8+ T cells that are observed in LCMV-infected animals that lack CD4+ T-cell help might not be due to a lack of direct interactions between CD4+ and CD8+ T cells, but to a failure to produce neutralizing antibodies against the virus, thereby allowing the infection to become chronic.

    Article  CAS  PubMed  Google Scholar 

  72. Younes, S. A. et al. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J. Exp. Med. 198, 1909–1922 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Day, C. L. & Walker, B. D. Progress in defining CD4 helper cell responses in chronic viral infections. J. Exp. Med. 198, 1773–1777 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Suzuki, H., Duncan, G. S., Takimoto, H. & Mak, T. W. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor β chain. J. Exp. Med. 185, 499–505 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858–861 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Van Parijs, L. & Abbas, A. K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280, 243–248 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  80. Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Wolf, M., Schimpl, A. & Hunig, T. Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25− and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms. Eur. J. Immunol. 31, 1637–1645 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Malek, T. R., Porter, B. O., Codias, E. K., Scibelli, P. & Yu, A. Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J. Immunol. 164, 2905–2914 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. D'Souza, W. N. & Lefrancois, L. IL-2 is not required for the initiation of CD8+ T cell cycling but sustains expansion. J. Immunol. 171, 5727–5735 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. D'Souza, W. N., Schluns, K. S., Masopust, D. & Lefrancois, L. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8+ T cell responses. J. Immunol. 168, 5566–5572 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Killeen, N., Sawada, S. & Littman, D. R. Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 12, 1547–1553 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Locksley, R. M., Reiner, S. L., Hatam, F., Littman, D. R. & Killeen, N. Helper T cells without CD4: control of leishmaniasis in CD4-deficient mice. Science 261, 1448–1451 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Tyznik, A. J., Sun, J. C. & Bevan, M. J. The CD8 population in CD4-deficient mice is heavily contaminated with MHC class II-restricted T cells. J. Exp. Med. 199, 559–565 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Grusby, M. J., Johnson, R. S., Papaioannou, V. E. & Glimcher, L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science 253, 1417–1420 (1991).

    Article  CAS  PubMed  Google Scholar 

  92. Cosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    Article  CAS  PubMed  Google Scholar 

  93. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Akira, S. Toll receptor families: structure and function. Semin. Immunol. 16, 1–2 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Kopp, E. & Medzhitov, R. Recognition of microbial infection by Toll-like receptors. Curr. Opin. Immunol. 15, 396–401 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Vabulas, R. M., Wagner, H. & Schild, H. Heat shock proteins as ligands of Toll-like receptors. Curr. Top. Microbiol. Immunol. 270, 169–184 (2002).

    CAS  PubMed  Google Scholar 

  98. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Albert, M. L. Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nature Rev. Immunol. 4, 223–231 (2004).

    Article  CAS  Google Scholar 

  100. Sun, J. C., Williams, M. A. & Bevan, M. J. CD4+ T cells are required for maintenance, not programming, of CD8+ memory T cells after acute infection. Nature Immunol. (in the press).

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  1. Department of Immunology, Howard Hughes Medical Institute, University of Washington, 1959 NE Pacific Street, Seattle, 98195-7650, Washington, USA

    Michael J. Bevan

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DATABASES

Entrez Gene

CCR7

CD4

CD8

CD40

CD40L

CD62 ligand

IL-2

IL-7

IL-15

Glossary

MIXED LYMPHOCYTE REACTION

A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

HISTOCOMPATIBILITY ANTIGEN H-Y

H-Y is a protein encoded on the Y chromosome. Female T cells respond to peptides derived from this protein and so H-Y is a male-specific histocompatibility antigen. Furthermore, T-cell receptors (TCRs) specific for this antigen have been cloned and used to generate distinct lines of TCR-transgenic mice.

IN VITRO RESTIMULATION

Some cytotoxic T lymphocyte responses are too weak to be measured directly ex vivo. In this case, spleen or blood cells can be stimulated for 5 days in culture with antigen to increase the number of antigen-specific CD8+ T cells.

T-CELL–B-CELL COOPERATION

For B cells to make high-affinity antibodies and switch from IgM to other immunoglobulin subclasses they require help from CD4+ T cells. Activated CD4+ T cells recognize endocytosed antigen presented by MHC class II molecules on the B cell and stimulate the B cell through CD40–CD40 ligand interactions.

PRIMARY RESPONSE

The response to initial immunization. In the case of CD8+ T-cell responses, this is usually measured at day 7–8 after immunization.

SECONDARY RESPONSE

When the first encounter with antigen has been cleared, a response to subsequent immunization with the same antigen is referred to as a secondary or recall response.

TETRAMER STAINING

Biotinylated monomeric MHC molecules are folded in vitro 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–MHC complex and can therefore be used to track antigen-specific T cells by flow cytometry.

ELISPOT

An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that can secrete cytokines (usually interferon-γ).

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Bevan, M. Helping the CD8+ T-cell response. Nat Rev Immunol 4, 595–602 (2004). https://doi.org/10.1038/nri1413

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