CD8 T-Cell Memory Differentiation during Acute and Chronic Viral Infections

  • Vandana Kalia
  • Surojit Sarkar
  • Rafi Ahmed
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 684)


CD8 T-cell responses play an important role in protection against intracellular pathogens. Memory CD8 T cells mediate rapid clearance of pathogens upon secondary infection owing to their elevated frequency, ready localization to peripheral sites of infection and their ability to rapidly expand and mount effector functions. Such potent long-lasting protective memory CD8 T cells develop in acute infections where antigen is effectively cleared. In contrast, chronic infections with persistently high viral loads are characterized by CD8 T-cell dysfunction. In this chapter we present our current understanding of signals and mechanisms that regulate the development of functional long-lived memory CD8 T cells during acute infections. This is discussed in the context of proposed models of memory differentiation and compared with CD8 T-cell exhaustion and altered T-cell homeostasis, as occurs during persistent viral infections.


Memory Cell Chronic Viral Infection Homeostatic Proliferation Functional Exhaustion Memory Precursor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Blattman JN, Antia R, Sourdive DJ et al. Estimating the precursor frequency of naive antigen-specific CD8 T-cells. J Exp Med 2002; 195(5):657–664.PubMedCrossRefGoogle Scholar
  2. 2.
    Butz EA, Bevan MJ. Massive expansion of antigen-specific CD8+ T-cells during an acute virus infection. Immunity 1998; 8(2):167–175.PubMedCrossRefGoogle Scholar
  3. 3.
    Doherty PC. The numbers game for virus-specific CD8+ T-cells. Science 1998; 280(5361):227.PubMedCrossRefGoogle Scholar
  4. 4.
    Murali-Krishna K, Altman JD, Suresh M et al. Counting antigen-specific CD8 T-cells: a reevaluation of bystander activation during viral infection. Immunity 1998; 8(2):177–187.PubMedCrossRefGoogle Scholar
  5. 5.
    Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2(4):251–262.PubMedCrossRefGoogle Scholar
  6. 6.
    Kalia V, Sarkar S, Gourley TS et al. Differentiation of memory B and T-cells. Curr Opin Immunol 2006; 18(3):255–264.PubMedCrossRefGoogle Scholar
  7. 7.
    Masopust D, Kaech SM, Wherry EJ et al. The role of programming in memory T-cell development. Curr Opin Immunol 2004; 16(2):217–225.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaech SM, Ahmed R. Memory CD8+ T-cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2001; 2(5):415–422.PubMedGoogle Scholar
  9. 9.
    Mercado R, Vijh S, Allen SE et al. Early programming of T-cell populations responding to bacterial infection. J Immunol 2000; 165(12):6833–6839.PubMedGoogle Scholar
  10. 10.
    van Stipdonk MJ, Hardenberg G, Bijker MS et al. Dynamic programming of CD8+ T-lymphocyte responses. Nat Immunol 2003; 4(4):361–365.PubMedCrossRefGoogle Scholar
  11. 11.
    van Stipdonk MJ, Lemmens EE, Schoenberger SP. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol 2001; 2(5):423–429.PubMedGoogle Scholar
  12. 12.
    Wong P, Pamer EG. Cutting edge: antigen-independent CD8 T-cell proliferation. J Immunol 2001; 166(10):5864–5868.PubMedGoogle Scholar
  13. 13.
    Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T-cells after infection. Nat Immunol 2002; 3(7):619–626.PubMedGoogle Scholar
  14. 14.
    Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol 2007; 25:171–192.PubMedCrossRefGoogle Scholar
  15. 15.
    Curtsinger JM, Schmidt CS, Mondino A et al. Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T-cells. J Immunol 1999; 162(6):3256–3262.PubMedGoogle Scholar
  16. 16.
    Schmidt CS, Mescher MF. Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T-cells in vivo. J Immunol 1999; 163(5):2561–2567.PubMedGoogle Scholar
  17. 17.
    Curtsinger JM, Johnson CM, Mescher MF. CD8 T-cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation and signal 3 cytokine. J Immunol 2003; 171(10):5165–5171.PubMedGoogle Scholar
  18. 18.
    Curtsinger JM, Lins DC, Johnson CM et al. Signal 3 tolerant CD8 T-cells degranulate in response to antigen but lack granzyme B to mediate cytolysis. J Immunol 2005; 175(7):4392–4399.PubMedGoogle Scholar
  19. 19.
    Valenzuela JO, Hammerbeck CD, Mescher MF. Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T-cells. J Immunol 2005; 174(2):600–604.PubMedGoogle Scholar
  20. 20.
    Mescher MF, Curtsinger JM, Agarwal P et al. Signals required for programming effector and memory development by CD8+ T-cells. Immunol Rev 2006; 211:81–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Curtsinger JM, Valenzuela JO, Agarwal P et al. Type I IFNs provide a third signal to CD8 T-cells to stimulate clonal expansion and differentiation. J Immunol 2005; 174(8):4465–4469.PubMedGoogle Scholar
  22. 22.
    Kolumam GA, Thomas S, Thompson LJ et al. Type I interferons act directly on CD8 T-cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 2005; 202(5):637–650.PubMedCrossRefGoogle Scholar
  23. 23.
    Zeng R, Spolski R, Finkelstein SE et al. Synergy of IL-21 and IL-15 in regulating CD8+ T-cell expansion and function. J Exp Med 2005; 201(1):139–148.PubMedCrossRefGoogle Scholar
  24. 24.
    Shedlock DJ, Shen H. Requirement for CD4 T-cell help in generating functional CD8 T-cell memory. Science 2003; 300(5617):337–339.PubMedCrossRefGoogle Scholar
  25. 25.
    Janssen EM, Lemmens EE, Wolfe T et al. CD4+ T-cells are required for secondary expansion and memory in CD8+ T-lymphocytes. Nature 2003; 421(6925):852–856.PubMedCrossRefGoogle Scholar
  26. 26.
    Sun JC, Bevan MJ. Defective CD8 T-cell memory following acute infection without CD4 T-cell help. Science 2003; 300(5617):339–342.PubMedCrossRefGoogle Scholar
  27. 27.
    Weant AE, Michalek RD, Khan IU et al. Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T-cell contraction. Immunity 2008; 28(2):218–230.PubMedCrossRefGoogle Scholar
  28. 28.
    Ahmed R. aBTR. Immunological memory. Immunological Reviews 2006; 211(1):5–7.Google Scholar
  29. 29.
    Badovinac VP, Harty JT. Manipulating the rate of memory CD8+ T-cell generation after acute infection. J Immunol 2007; 179(1):53–63.PubMedGoogle Scholar
  30. 30.
    Marzo AL, Klonowski KD, Le Bon A et al. Initial T-cell frequency dictates memory CD8+ T-cell lineage commitment. Nat Immunol 2005; 6(8):793–799.PubMedCrossRefGoogle Scholar
  31. 31.
    Lefrancois L. Development, trafficking and function of memory T-cell subsets. Immunol Rev 2006; 211:93–103.PubMedCrossRefGoogle Scholar
  32. 32.
    Huster KM, Busch V, Schiemann 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 2004; 101(15):5610–5615.PubMedCrossRefGoogle Scholar
  33. 33.
    Joshi NS, Cui W, Chandele A et al. Inflammation directs memory precursor and short-lived effector CD8(+) T-cell fates via the graded expression of T-bet transcription factor. Immunity 2007; 27(2):281–295.PubMedCrossRefGoogle Scholar
  34. 34.
    Kaech SM, Tan JT, Wherry EJ et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T-cells that give rise to long-lived memory cells. Nat Immunol 2003; 4(12):1191–1198.PubMedCrossRefGoogle Scholar
  35. 35.
    Sarkar S, Kalia V, Haining WN et al. Functional and genomic profiling of effector CD8 T-cell subsets with distinct memory fates. J Exp Med 2008; 205(3):625–640.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang M, Byrne S, Liu N et al. Differential survival of cytotoxic T-cells and memory cell precursors. J Immunol 2007; 178(6):3483–3491.PubMedGoogle Scholar
  37. 37.
    Klonowski KD, Lefrancois L. The CD8 memory T-cell subsystem: integration of homeostatic signaling during migration. Semin Immunol 2005; 17(3):219–229.PubMedCrossRefGoogle Scholar
  38. 38.
    Ma A, Koka R, Burkett P. Diverse functions of IL-2, IL-15 and IL-7 in lymphoid homeostasis. Annu Rev Immunol 2006; 24:657–679.PubMedCrossRefGoogle Scholar
  39. 39.
    Surh CD, Sprent J. Homeostasis of naive and memory T-cells. Immunity 2008; 29(6):848–862.PubMedCrossRefGoogle Scholar
  40. 40.
    Becker TC, Wherry EJ, Boone D et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T-cells. J Exp Med 2002; 195(12):1541–1548.PubMedCrossRefGoogle Scholar
  41. 41.
    Yajima T, Yoshihara K, Nakazato K et al. IL-15 regulates CD8+ T-cell contraction during primary infection. J Immunol 2006; 176(1):507–515.PubMedGoogle Scholar
  42. 42.
    Hand TW, Morre M, Kaech SM. Expression of IL-7 receptor alpha is necessary but not sufficient for the formation of memory CD8 T-cells during viral infection. Proc Natl Acad Sci USA 2007; 104(28):11730–11735.PubMedCrossRefGoogle Scholar
  43. 43.
    Klonowski KD, Williams KJ, Marzo AL et al. Cutting edge: IL-7-independent regulation of IL-7 receptor alpha expression and memory CD8 T-cell development. J Immunol 2006; 177(7):4247–4251.PubMedGoogle Scholar
  44. 44.
    Sun JC, Lehar SM, Bevan MJ. Augmented IL-7 signaling during viral infection drives greater expansion of effector T-cells but does not enhance memory. J Immunol 2006; 177(7):4458–4463.PubMedGoogle Scholar
  45. 45.
    Williams MA, Holmes BJ, Sun JC et al. Developing and maintaining protective CD8+ memory T-cells. Immunol Rev 2006; 211:146–153.PubMedCrossRefGoogle Scholar
  46. 46.
    Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T-cells. Nature 2006; 441(7095):890–893.PubMedCrossRefGoogle Scholar
  47. 47.
    Kaech SM, Hemby S, Kersh E et al. Molecular and functional profiling of memory CD8 T-cell differentiation. Cell 2002; 111(6):837–851.PubMedCrossRefGoogle Scholar
  48. 48.
    Wherry EJ, Teichgraber V, Becker TC et al. Lineage relationship and protective immunity of memory CD8 T-cell subsets. Nat Immunol 2003; 4(3):225–234.PubMedCrossRefGoogle Scholar
  49. 49.
    Roberts AD, Ely KH, Woodland DL. Differential contributions of central and effector memory T-cells to recall responses. J Exp Med 2005; 202(1):123–133.PubMedCrossRefGoogle Scholar
  50. 49a.
    Araki K, Turner AP, Shaffer VO, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. Jul 2 2009;460(7251):108–112.Google Scholar
  51. 49b.
    Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. Jul 2 2009;460(7251):103–107.Google Scholar
  52. 50.
    Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T-cell subsets. Curr Opin Immunol 2005; 17(3):326–332.PubMedCrossRefGoogle Scholar
  53. 51.
    Masopust D, Vezys V, Marzo AL et al. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291(5512):2413–2417.PubMedCrossRefGoogle Scholar
  54. 52.
    Pearce EL, Shen H. Making sense of inflammation, epigenetics and memory CD8+ T-cell differentiation in the context of infection. Immunol Rev 2006; 211:197–202.PubMedCrossRefGoogle Scholar
  55. 53.
    Wilson CB, Makar KW, Shnyreva M et al. DNA methylation and the expanding epigenetics of T-cell lineage commitment. Semin Immunol 2005; 17(2):105–119.PubMedCrossRefGoogle Scholar
  56. 54.
    Kersh EN, Fitzpatrick DR, Murali-Krishna K et al. Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T-cells. J Immunol 2006; 176(7):4083–4093.PubMedGoogle Scholar
  57. 55.
    Intlekofer AM, John Wherry E, Reiner SL. Not-so-great expectations: re-assessing the essence of T-cell memory. Immunol Rev 2006; 211:203–213.PubMedCrossRefGoogle Scholar
  58. 56.
    Intlekofer AM, Takemoto N, Wherry EJ et al. Effector and memory CD8+ T-cell fate coupled by T-bet and eomesodermin. Nat Immunol 2005; 6(12):1236–1244.PubMedCrossRefGoogle Scholar
  59. 57.
    Manders PM, Hunter PJ, Telaranta AI et al. BCL6b mediates the enhanced magnitude of the secondary response of memory CD8+ T-lymphocytes. Proc Natl Acad Sci USA 2005; 102(21):7418–7425.PubMedCrossRefGoogle Scholar
  60. 58.
    Kersh EN, Kaech SM, Onami TM et al. TCR signal transduction in antigen-specific memory CD8 T-cells. J Immunol 2003; 170(11):5455–5463.PubMedGoogle Scholar
  61. 59.
    Latner DR, Kaech SM, Ahmed R. Enhanced expression of cell cycle regulatory genes in virus-specific memory CD8+ T-cells. J Virol 2004; 78(20):10953–10959.PubMedCrossRefGoogle Scholar
  62. 60.
    Veiga-Fernandes H, Rocha B. High expression of active CDK6 in the cytoplasm of CD8 memory cells favors rapid division. Nat Immunol 2004; 5(1):31–37.PubMedCrossRefGoogle Scholar
  63. 61.
    Opferman JT, Ober BT, Ashton-Rickardt PG. Linear differentiation of cytotoxic effectors into memory T-lymphocytes. Science 1999; 283(5408):1745–1748.PubMedCrossRefGoogle Scholar
  64. 62.
    Jacob J, Baltimore D. Modelling T-cell memory by genetic marking of memory T-cells in vivo. Nature 1999; 399(6736):593–597.PubMedCrossRefGoogle Scholar
  65. 63.
    Bannard O, Kraman M, Fearon DT. Secondary replicative function of CD8+ T-cells that had developed an effector phenotype. Science 2009; 323(5913):505–509.PubMedCrossRefGoogle Scholar
  66. 64.
    Chang JT, Palanivel VR, Kinjyo I et al. Asymmetric T-lymphocyte division in the initiation of adaptive immune responses. Science 2007; 315(5819):1687–1691.PubMedCrossRefGoogle Scholar
  67. 65.
    Lauvau G, Vijh S, Kong P et al. Priming of memory but not effector CD8 T-cells by a killed bacterial vaccine. Science 2001; 294(5547):1735–1739.PubMedCrossRefGoogle Scholar
  68. 66.
    Manjunath N, Shankar P, Wan J et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T-lymphocytes. J Clin Invest 2001; 108(6):871–878.PubMedGoogle Scholar
  69. 67.
    Lanzavecchia A, Sallusto F. Dynamics of T-lymphocyte responses: intermediates, effectors and memory cells. Science 2000; 290(5489):92–97.PubMedCrossRefGoogle Scholar
  70. 68.
    Fearon DT, Manders P, Wagner SD. Arrested differentiation, the self-renewing memory lymphocyte and vaccination. Science 2001; 293(5528):248–250.PubMedCrossRefGoogle Scholar
  71. 69.
    Wong P, Lara-Tejero M, Ploss A et al. Rapid development of T-cell memory. J Immunol 2004; 172(12):7239–7245.PubMedGoogle Scholar
  72. 70.
    Zhang Y, Joe G, Hexner E et al. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med 2005; 11(12):1299–1305.PubMedCrossRefGoogle Scholar
  73. 71.
    van Leeuwen EM, de Bree GJ, ten Berge IJ et al. Human virus-specific CD8+ T-cells: diversity specialists. Immunol Rev 2006; 211:225–235.PubMedCrossRefGoogle Scholar
  74. 72.
    Teixeiro E, Daniels MA, Hamilton SE et al. Different T-cell receptor signals determine CD8+ memory versus effector development. Science 2009; 323(5913):502–505.PubMedCrossRefGoogle Scholar
  75. 73.
    Lefrancois L, Masopust D. The road not taken: memory T-cell fate ‘decisions’. Nat Immunol 2009; 10(4):369–370.PubMedCrossRefGoogle Scholar
  76. 74.
    Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science 1996; 272(5258):54–60.PubMedCrossRefGoogle Scholar
  77. 75.
    Gett AV, Sallusto F, Lanzavecchia A et al. T-cell fitness determined by signal strength. Nat Immunol 2003; 4(4):355–360.PubMedCrossRefGoogle Scholar
  78. 76.
    Lanzavecchia A, Sallusto F. Antigen decoding by T-lymphocytes: from synapses to fate determination. Nat Immunol 2001; 2(6):487–492.PubMedCrossRefGoogle Scholar
  79. 77.
    Lanzavecchia A, Sallusto F. Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol 2002; 2(12):982–987.PubMedCrossRefGoogle Scholar
  80. 78.
    Williams MA, Bevan MJ. Shortening the infectious period does not alter expansion of CD8 T-cells but diminishes their capacity to differentiate into memory cells. J Immunol 2004; 173(11):6694–6702.PubMedGoogle Scholar
  81. 79.
    van Faassen H, Saldanha M, Gilbertson D et al. Reducing the stimulation of CD8+ T-cells during infection with intracellular bacteria promotes differentiation primarily into a central (CD62LhighCD44high) subset. J Immunol 2005; 174(9):5341–5350.PubMedGoogle Scholar
  82. 80.
    Jelley-Gibbs DM, Dibble JP, Filipson S et al. Repeated stimulation of CD4 effector T-cells can limit their protective function. J Exp Med 2005; 201(7):1101–1112.PubMedCrossRefGoogle Scholar
  83. 81.
    D’Souza WN HS. Cutting edge: latecomer CD8 T-cells are imprinted with a unique differentiation program. J Immunol 2006; 177(2):777–781.PubMedGoogle Scholar
  84. 82.
    Jelley-Gibbs DM, Dibble JP, Brown DM et al. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T-cell response. J Immunol 2007; 178(12):7563–7570.PubMedGoogle Scholar
  85. 83.
    Sarkar S, Teichgraber V, Kalia V et al. Strength of stimulus and clonal competition impact the rate of memory CD8 T-cell differentiation. J Immunol 2007; 179(10):6704–6714.PubMedGoogle Scholar
  86. 84.
    Badovinac VP, Haring JS, Harty JT. Initial T-cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T-cell response to infection. Immunity 2007; 26(6):827–841.PubMedCrossRefGoogle Scholar
  87. 85.
    Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol 2004; 78(11):5535–5545.PubMedCrossRefGoogle Scholar
  88. 86.
    Zajac AJ, Blattman JN, Murali-Krishna K et al. Viral immune evasion due to persistence of activated T-cells without effector function. J Exp Med 1998; 188(12):2205–2213.PubMedCrossRefGoogle Scholar
  89. 87.
    Wherry EJ, Blattman JN, Murali-Krishna K et al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003; 77(8):4911–4927.PubMedCrossRefGoogle Scholar
  90. 88.
    Wherry EJ, Barber DL, Kaech SM et al. Antigen-independent memory CD8 T-cells do not develop during chronic viral infection. Proc Natl Acad Sci USA 2004; 101(45):16004–16009.PubMedCrossRefGoogle Scholar
  91. 89.
    Shin H, Wherry EJ. CD8 T-cell dysfunction during chronic viral infection. Curr Opin Immunol 2007; 19(4):408–415.PubMedCrossRefGoogle Scholar
  92. 90.
    Moser JM, Altman JD, Lukacher AE. Antiviral CD8+ T-cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T-cells. J Exp Med 2001; 193(5):595–606.PubMedCrossRefGoogle Scholar
  93. 91.
    Dittmer U, He H, Messer RJ et al. Functional impairment of CD8(+) T-cells by regulatory T-cells during persistent retroviral infection. Immunity 2004; 20(3):293–303.PubMedCrossRefGoogle Scholar
  94. 92.
    Krebs P, Scandella E, Odermatt B et al. Rapid functional exhaustion and deletion of CTL following immunization with recombinant adenovirus. J Immunol 2005; 174(8):4559–4566.PubMedGoogle Scholar
  95. 93.
    Bergmann CC, Altman JD, Hinton D et al. Inverted immunodominance and impaired cytolytic function of CD8+ T-cells during viral persistence in the central nervous system. J Immunol 1999; 163(6):3379–3387.PubMedGoogle Scholar
  96. 94.
    Vogel TU, Allen TM, Altman JD et al. Functional impairment of simian immunodeficiency virus-specific CD8+ T-cells during the chronic phase of infection. J Virol 2001; 75(5):2458–2461.PubMedCrossRefGoogle Scholar
  97. 95.
    Becker TC, Coley SM, Wherry EJ et al. Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T-cells. J Immunol 2005; 174(3):1269–1273.PubMedGoogle Scholar
  98. 96.
    Di Rosa F, Pabst R. The bone marrow: a nest for migratory memory T-cells. Trends Immunol 2005; 26(7):360–366.PubMedCrossRefGoogle Scholar
  99. 97.
    Fuller MJ, Hildeman DA, Sabbaj S et al. Cutting edge: emergence of CD127high functionally competent memory T-cells is compromised by high viral loads and inadequate T-cell help. J Immunol 2005; 174(10):5926–5930.PubMedGoogle Scholar
  100. 98.
    Lang KS, Recher M, Navarini AA et al. Inverse correlation between IL-7 receptor expression and CD8 T-cell exhaustion during persistent antigen stimulation. Eur J Immunol 2005; 35(3):738–745.PubMedCrossRefGoogle Scholar
  101. 99.
    Shin H, Blackburn SD, Blattman JN et al. Viral antigen and extensive division maintain virus-specific CD8 T-cells during chronic infection. J Exp Med 2007; 204(4):941–949.PubMedCrossRefGoogle Scholar
  102. 100.
    Obar JJ, Crist SG, Leung EK et al. IL-15-independent proliferative renewal of memory CD8+ T-cells in latent gammaherpesvirus infection. J Immunol 2004; 173(4):2705–2714.PubMedGoogle Scholar
  103. 101.
    Brooks DG, McGavern DB, Oldstone MB. Reprogramming of antiviral T-cells prevents inactivation and restores T-cell activity during persistent viral infection. J Clin Invest 2006; 116(6):1675–1685.PubMedCrossRefGoogle Scholar
  104. 102.
    Wherry EJ, Ha SJ, Kaech SM et al. Molecular signature of CD8+ T-cell exhaustion during chronic viral infection. Immunity 2007; 27(4):670–684.PubMedCrossRefGoogle Scholar
  105. 103.
    Blackburn SD, Shin H, Haining WN et al. Coregulation of CD8+ T-cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10(1):29–37.PubMedCrossRefGoogle Scholar
  106. 104.
    Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T-cells during chronic viral infection. Nature 2005.Google Scholar
  107. 105.
    Radziewicz H, Ibegbu CC, Fernandez ML et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007; 81(6):2545–2553.PubMedCrossRefGoogle Scholar
  108. 106.
    Urbani S, Amadei B, Tola D et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80(22):11398–11403.PubMedCrossRefGoogle Scholar
  109. 107.
    Radziewicz H, Uebelhoer L, Bengsch B et al. Memory CD8+ T-cell differentiation in viral infection: a cell for all seasons. World J Gastroenterol 2007; 13(36):4848–4857.PubMedGoogle Scholar
  110. 108.
    Day CL, Kaufmann DE, Kiepiela P et al. PD-1 expression on HIV-specific T-cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443(7109):350–354.PubMedCrossRefGoogle Scholar
  111. 109.
    Trautmann L, Janbazian L, Chomont N et al. Upregulation of PD-1 expression on HIV-specific CD8+ T-cells leads to reversible immune dysfunction. Nat Med 2006; 12(10):1198–1202.PubMedCrossRefGoogle Scholar
  112. 110.
    Petrovas C, Casazza JP, Brenchley JM et al. PD-1 is a regulator of virus-specific CD8+ T-cell survival in HIV infection. J Exp Med 2006; 203(10):2281–2292.PubMedCrossRefGoogle Scholar
  113. 111.
    Zhang JY, Zhang Z, Wang X et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 2007; 109(11):4671–4678.PubMedCrossRefGoogle Scholar
  114. 112.
    Brooks DG, Trifilo MJ, Edelmann KH et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006; 12(11):1301–1309.PubMedCrossRefGoogle Scholar
  115. 113.
    Ejrnaes M, Filippi CM, Martinic MM et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 2006; 203(11):2461–2472.PubMedCrossRefGoogle Scholar
  116. 114.
    Knapp S, Hennig BJ, Frodsham AJ et al. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics 2003; 55(6):362–369.PubMedCrossRefGoogle Scholar
  117. 115.
    Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25(2):195–201.PubMedCrossRefGoogle Scholar
  118. 116.
    Rouse BT, Sarangi PP, Suvas S. Regulatory T-cells in virus infections. Immunol Rev 2006; 212:272–286.PubMedCrossRefGoogle Scholar
  119. 117.
    Mempel TR, Pittet MJ, Khazaie K et al. Regulatory T-cells reversibly suppress cytotoxic T-cell function independent of effector differentiation. Immunity 2006; 25(1):129–141.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Emory Vaccine Center, EmoryUniversity School of MedicineAtlantaUSA

Personalised recommendations