Impact of Aging on T Cell Repertoire and Immunity

  • Marcia A. BlackmanEmail author
  • David L. Woodland


Immune function declines with age, resulting in increased susceptibility to infection and reduced vaccination efficacy. A major contributing factor to impaired immunity with ageing is age-associated changes in the repertoire of T cells. Specifically, production of naïve T cells declines due to thymic atrophy, and the memory compartment increases progressively with age until it greatly exceeds the naïve compartment. In addition, the memory compartment is further perturbed by the frequent appearance of clonal expansions in the memory CD8+ T cells. As a consequence, the naïve compartment becomes constrained in size, and there is associated loss of repertoire diversity that impacts the ability to respond to new infections and vaccination and can impair previously established memory. A major driving force of clonal expansions in humans is infection with the persistent β-herpesvirus, cytomegalovirus (CMV), with CMV-specific CD8+ T cells progressively dominating the repertoire. In this chapter, we review important advances in our understanding of the impact of age-associated changes in the repertoire on immune function and discuss possible therapeutic approaches to ameliorate immunosenescence.


Influenza Virus Memory Cell Aged Mouse Young Mouse Reactivation Event 
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.


  1. Agrawal A, Agrawal S, Tay J et al (2008) Biology of dendritic cells in aging. J Clin Immunol 28(1):14–20PubMedGoogle Scholar
  2. Ahmed M, Lanzer KG, Yager EJ et al (2009) Clonal expansions and loss of receptor diversity in the naive CD8+ T cell repertoire of aged mice. J Immunol 182(2):784–792PubMedGoogle Scholar
  3. Alexander T, Thiel A, Rosen O et al (2009) Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113(1):214–223PubMedGoogle Scholar
  4. Almanzar G, Schwaiger S, Jenewein B et al (2005) Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol 79(6):3675–3683PubMedGoogle Scholar
  5. Appay V, Dunbar PR, Callan M et al (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8(4):379–385PubMedGoogle Scholar
  6. Arstila TP, Casrouge A, Baron V et al (1999) A direct estimate of the human alphabeta T cell receptor diversity. Science 286(5441):958–961PubMedGoogle Scholar
  7. Aspinall R, Mitchell W (2008) Reversal of age-associated thymic atrophy: treatments, delivery, and side effects. Exp Gerontol 43(7):700–705PubMedGoogle Scholar
  8. Barton ES, White DW, Cathelyn JS et al (2007) Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447(7142):326–329PubMedGoogle Scholar
  9. Beswick M, Pachnio A, Lauder SN et al (2013) Antiviral therapy can reverse the development of immune senescence in elderly mice with latent cytomegalovirus infection. J Virol 87(2):779–789PubMedGoogle Scholar
  10. Blackman MA, Woodland DL (2011) The narrowing of the CD8+ T cell repertoire in old age. Curr Opin Immunol 23(4):537–542PubMedGoogle Scholar
  11. Brunner S, Herndler-Brandstetter D, Weinberger B et al (2010) Persistent viral infections and immune aging. Ageing Res Rev 10(3):362–369PubMedGoogle Scholar
  12. Bunztman A, Vincent BG, Krovi H et al (2012) The LCMV gp33-specific memory T cell repertoire narrows with age. Immun Ageing 9(1):17PubMedGoogle Scholar
  13. Callahan JE, Kappler JW, Marrack P (1993) Unexpected expansions of CD8+ −bearing cells in old mice. J Immunol 151(12):6657–6669PubMedGoogle Scholar
  14. Casrouge A, Beaudoing E, Dalle S et al (2000) Size estimate of the alpha beta TCR repertoire of naive mouse splenocytes. J Immunol 164(11):5782–5787PubMedGoogle Scholar
  15. Cicin-Sain L, Messaoudi I, Park B et al (2007) Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 104(50):19960–19965PubMedGoogle Scholar
  16. Cicin-Sain L, Smyk-Pearson S, Currier N et al (2010) Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J Immunol 184(12):6739–6745PubMedGoogle Scholar
  17. Cicin-Sain L, Brien JD, Uhrlaub JL et al (2012) Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog 8(8):e1002849PubMedGoogle Scholar
  18. Clambey ET, Kappler JW, Marrack P (2007) CD8+ T cell clonal expansions & aging: a heterogeneous phenomenon with a common outcome. Exp Gerontol 42(5):407–411PubMedGoogle Scholar
  19. Clambey ET, White J, Kappler JW et al (2008) Identification of two major types of age-associated CD8+ clonal expansions with highly divergent properties. Proc Natl Acad Sci U S A 105(35):12997–13002PubMedGoogle Scholar
  20. Coler RN, Baldwin SL, Shaverdian N et al (2010) A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One 5(10):e13677PubMedGoogle Scholar
  21. Colonna-Romano G, Akbar AN, Aquino A et al (2007) Impact of CMV and EBV seropositivity on CD8+ T lymphocytes in an old population from West-Sicily. Exp Gerontol 42(10):995–1002PubMedGoogle Scholar
  22. Connor LM, Kohlmeier JE, Ryan L et al (2012) Early dysregulation of the memory CD8+ T cell repertoire leads to compromised immune responses to secondary viral infection in the aged. Immun Ageing 9(1):28PubMedGoogle Scholar
  23. Day EK, Carmichael AJ, ten Berge IJ et al (2007) Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J Immunol 179(5):3203–3213PubMedGoogle Scholar
  24. Decman V, Laidlaw BJ, Dimenna LJ et al (2010) Cell-intrinsic defects in the proliferative response of antiviral memory CD8+ T cells in aged mice upon secondary infection. J Immunol 184(9):5151–5159PubMedGoogle Scholar
  25. Decman V, Laidlaw BJ, Doering TA et al (2012) Defective CD8+ T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. J Immunol 188(4):1933–1941PubMedGoogle Scholar
  26. den Braber I, Mugwagwa T, Vrisekoop N et al (2012) Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36(2):288–297Google Scholar
  27. Derhovanessian E, Maier AB, Hahnel K et al (2011) Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. J Gen Virol 92(Pt 12):2746–2756PubMedGoogle Scholar
  28. Derhovanessian E, Theeten H, Hahnel K et al (2012) Cytomegalovirus-associated accumulation of late-differentiated CD4+ T-cells correlates with poor humoral response to influenza vaccination. Vaccine 31(4):685–690PubMedGoogle Scholar
  29. Dudakov JA, Hanash AM, Jenq RR et al (2012) Interleukin-22 drives endogenous thymic regeneration in mice. Science 336(6077):91–95PubMedGoogle Scholar
  30. Effros RB, Walford RL (1983) Diminished T-cell response to influenza virus in aged mice. Immunology 49(2):387–392PubMedGoogle Scholar
  31. Effros RB, Allsopp R, Chiu CP et al (1996) Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10(8):F17–F22PubMedGoogle Scholar
  32. Effros RB, Cai Z, Linton PJ (2003) CD8+ T cells and aging. Crit Rev Immunol 23(1–2):45–64PubMedGoogle Scholar
  33. Ely KH, Ahmed M, Kohlmeier JE et al (2007a) Antigen-specific CD8+ T cell clonal expansions develop from memory T cell pools established by acute respiratory virus infections. J Immunol 179(6):3535–3542PubMedGoogle Scholar
  34. Ely KH, Roberts AD, Kohlmeier JE et al (2007b) Aging and CD8+ T cell immunity to respiratory virus infections. Exp Gerontol 42(5):427–431PubMedGoogle Scholar
  35. Feuchtinger T, Opherk K, Bethge WA et al (2010) Adoptive transfer of pp 65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116(20):4360–4367PubMedGoogle Scholar
  36. Finch CE, Crimmins EM (2004) Inflammatory exposure and historical changes in human life-spans. Science 305(5691):1736–1739PubMedGoogle Scholar
  37. Ge Q, Hu H, Eisen HN et al (2002) Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. Proc Natl Acad Sci U S A 99(5):2989–2994PubMedGoogle Scholar
  38. Gibson KL, Wu YC, Barnett Y et al (2009) B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8(1):18–25PubMedGoogle Scholar
  39. Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opin Immunol 17(5):468–475PubMedGoogle Scholar
  40. Goronzy JJ, Fulbright JW, Crowson CS et al (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75(24):12182–12187PubMedGoogle Scholar
  41. Goronzy JJ, Lee WW, Weyand CM (2007) Aging and T-cell diversity. Exp Gerontol 42(5):400–406PubMedGoogle Scholar
  42. Hadrup SR, Strindhall J, Kollgaard T et al (2006) Longitudinal studies of clonally expanded CD8+ T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 176(4):2645–2653PubMedGoogle Scholar
  43. Hansen SG, Powers CJ, Richards R et al (2010) Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science 328(5974):102–106PubMedGoogle Scholar
  44. Haynes L (2005) The effect of aging on cognate function and development of immune memory. Curr Opin Immunol 17(5):476–479PubMedGoogle Scholar
  45. Haynes L, Swain SL (2006) Why aging T cells fail: implications for vaccination. Immunity 24(6):663–666PubMedGoogle Scholar
  46. Haynes L, Eaton SM, Burns EM et al (2003) CD4+ T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci U S A 100(25):15053–15058PubMedGoogle Scholar
  47. Heng TS, Chidgey AP, Boyd RL (2010) Getting back at nature: understanding thymic development and overcoming its atrophy. Curr Opin Pharmacol 10(4):425–433PubMedGoogle Scholar
  48. Huster KM, Stemberger C, Gasteiger G et al (2009) Cutting edge: memory CD8+ T cell compartment grows in size with immunological experience but nevertheless can lose function. J Immunol 183(11):6898–6902PubMedGoogle Scholar
  49. Jankovic V, Messaoudi I, Nikolich-Zugich J (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4+ and CD8+ subsets. Blood 102(9):3244–3251PubMedGoogle Scholar
  50. Jiang J, Bennett AJ, Fisher E et al (2009) Limited expansion of virus-specific CD8+ T cells in the aged environment. Mech Ageing Dev 130(11–12):713–721PubMedGoogle Scholar
  51. Jiang J, Fisher EM, Murasko DM (2011) CD8+ T cell responses to influenza virus infection in aged mice. Ageing Res Rev 10(4):422–427PubMedGoogle Scholar
  52. Kapasi ZF, Murali-Krishna K, McRae ML et al (2002) Defective generation but normal maintenance of memory T cells in old mice. Eur J Immunol 32:1567–1573PubMedGoogle Scholar
  53. Karrer U, Sierro S, Wagner M et al (2003) Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J Immunol 170(4):2022–2029PubMedGoogle Scholar
  54. Kedzierska K, La Gruta NL, Davenport MP et al (2005) Contribution of T cell receptor affinity to overall avidity for virus-specific CD8+ T cell responses. Proc Natl Acad Sci U S A 102(32):11432–11437PubMedGoogle Scholar
  55. Khan N, Shariff N, Cobbold M et al (2002) Cytomegalovirus seropositivity drives the CD8+ T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169(4):1984–1992PubMedGoogle Scholar
  56. Khan N, Hislop A, Gudgeon N et al (2004) Herpesvirus-specific CD8+ T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 173(12):7481–7489PubMedGoogle Scholar
  57. Klenerman P, Dunbar PR (2008) CMV and the art of memory maintenance. Immunity 29(4):520–522PubMedGoogle Scholar
  58. Kohlmeier JE, Connor LM, Roberts AD et al (2010) Nonmalignant clonal expansions of memory CD8+ T cells that arise with age vary in their capacity to mount recall responses to infection. J Immunol 185(6):3456–3462PubMedGoogle Scholar
  59. Ku CC, Kotzin B, Kappler J et al (1997) CD8+ T-cell clones in old mice. Immunol Rev 160:139–144PubMedGoogle Scholar
  60. Ku CC, Kappler J, Marrack P (2001) The growth of the very large CD8+ T cell clones in older mice is controlled by cytokines. J Immunol 166(4):2186–2193PubMedGoogle Scholar
  61. Lages CS, Suffia I, Velilla PA et al (2008) Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 181(3):1835–1848PubMedGoogle Scholar
  62. Lang A, Brien JD, Messaoudi I et al (2008) Age-related dysregulation of CD8+ T cell memory specific for a persistent virus is independent of viral replication. J Immunol 180(7):4848–4857PubMedGoogle Scholar
  63. Lang A, Brien JD, Nikolich-Zugich J (2009) Inflation and long-term maintenance of CD8+ T cells responding to a latent herpesvirus depend upon establishment of latency and presence of viral antigens. J Immunol 183(12):8077–8087PubMedGoogle Scholar
  64. Lee JB, Oelke M, Ramachandra L et al (2011) Decline of influenza-specific CD8+ T cell repertoire in healthy geriatric donors. Immun Ageing 8:6PubMedGoogle Scholar
  65. LeMaoult J, Messaoudi I, Manavalan JS et al (2000) Age-related dysregulation in CD8+ T cell homeostasis: kinetics of a diversity loss. J Immunol 165(5):2367–2373PubMedGoogle Scholar
  66. Li SP, Cai Z, Shi W et al (2002) Early antigen-specific response by naive CD8+ T cells is not altered with aging. J Immunol 168:6120–6127PubMedGoogle Scholar
  67. Lynch HE, Goldberg GL, Chidgey A et al (2009) Thymic involution and immune reconstitution. Trends Immunol 30(7):366–373PubMedGoogle Scholar
  68. Mackall CL, Gress RE (1997) Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev 157:61–72PubMedGoogle Scholar
  69. Mattison JA, Roth GS, Beasley TM et al (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489(7415):318–321PubMedGoogle Scholar
  70. Maue AC, Eaton SM, Lanthier PA et al (2009) Proinflammatory adjuvants enhance the cognate helper activity of aged CD4+ T cells. J Immunol 182(10):6129–6135PubMedGoogle Scholar
  71. McElhaney JE, Xie D, Hager WD et al (2006) T cell responses are better correlates of vaccine protection in the elderly. J Immunol 176(10):6333–6339PubMedGoogle Scholar
  72. McElhaney JE, Ewen C, Zhou X et al (2009) Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine 27(18):2418–2425PubMedGoogle Scholar
  73. Mekker A, Tchang VS, Haeberli L et al (2012) Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog 8(8):e1002850PubMedGoogle Scholar
  74. Messaoudi I, Guevara Patino JA, Dyall R et al (2002) Direct link between mhc polymorphism, T cell avidity, and diversity in immune defense. Science 298(5599):1797–1800PubMedGoogle Scholar
  75. Messaoudi I, Lemaoult J, Guevara-Patino JA et al (2004) Age-related CD8+ T cell clonal expansions constrict CD8+ T cell repertoire and have the potential to impair immune defense. J Exp Med 200(10):1347–1358PubMedGoogle Scholar
  76. Messaoudi I, Warner J, Fischer M et al (2006a) Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci U S A 103(51):19448–19453PubMedGoogle Scholar
  77. Messaoudi I, Warner J, Nikolich-Zugich J (2006b) Age-related CD8+ T cell clonal expansions express elevated levels of CD122 and CD127 and display defects in perceiving homeostatic signals. J Immunol 177(5):2784–2792PubMedGoogle Scholar
  78. Miller RA (1996) The aging immune system: primer and prospectus. Science 273(5271):70–74PubMedGoogle Scholar
  79. Monteiro J, Batliwalla F, Ostrer H et al (1996) Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28 + CD8+ counterparts. J Immunol 156(10):3587–3590PubMedGoogle Scholar
  80. Moon JJ, Chu HH, Pepper M et al (2007) Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27(2):203–213PubMedGoogle Scholar
  81. Munks MW, Gold MC, Zajac AL et al (2006) Genome-wide analysis reveals a highly diverse CD8+ T cell response to murine cytomegalovirus. J Immunol 176(6):3760–3766PubMedGoogle Scholar
  82. Murasko DM, Jiang J (2005) Response of aged mice to primary virus infections. Immunol Rev 205:285–296PubMedGoogle Scholar
  83. Naylor K, Li G, Vallejo AN et al (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174(11):7446–7452PubMedGoogle Scholar
  84. Nishioka T, Shimizu J, Iida R et al (2006) CD4 + CD25 + Foxp3+ T cells and CD4 + CD25-Foxp3+ T cells in aged mice. J Immunol 176(11):6586–6593PubMedGoogle Scholar
  85. Obar JJ, Khanna KM, Lefrancois L (2008) Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28(6):859–869PubMedGoogle Scholar
  86. Ouyang Q, Wagner WM, Walter S et al (2003) An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein-Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness. Mech Ageing Dev 124(4):477–485PubMedGoogle Scholar
  87. Ouyang Q, Wagner WM, Zheng W et al (2004) Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol 39(4):607–613PubMedGoogle Scholar
  88. Pawelec G (2005) Immunosenescence and vaccination. Immun Ageing 2:16PubMedGoogle Scholar
  89. Pawelec G, Akbar A, Caruso C et al (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268PubMedGoogle Scholar
  90. Pawelec G, Derhovanessian E, Larbi A et al (2009) Cytomegalovirus and human immunosenescence. Rev Med Virol 19(1):47–56PubMedGoogle Scholar
  91. Pawelec G, Larbi A, Derhovanessian E (2010) Senescence of the human immune system. J Comp Pathol 142(Suppl 1):S39–S44PubMedGoogle Scholar
  92. Pitcher CJ, Hagen SI, Walker JM et al (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168(1):29–43PubMedGoogle Scholar
  93. Po JL, Gardner EM, Anaraki F et al (2002) Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev 123(8):1167–1181PubMedGoogle Scholar
  94. Posnett DN, Sinha R, Kabak S et al (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J Exp Med 179(2):609–618PubMedGoogle Scholar
  95. Roberts AD, Ely KH, Woodland DL (2005) Differential contributions of central and effector memory T cells to recall responses. J Exp Med 202(1):123–133PubMedGoogle Scholar
  96. Roberts ET, Haan MN, Dowd JB et al (2010) Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol 172(4):363–371PubMedGoogle Scholar
  97. Rudd BD, Venturi V, Davenport MP et al (2011a) Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J Immunol 186(4):2056–2064PubMedGoogle Scholar
  98. Rudd BD, Venturi V, Li G et al (2011b) Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc Natl Acad Sci U S A 108(33):13694–13699PubMedGoogle Scholar
  99. Saurwein-Teissl M, Lung TL, Marx F et al (2002) Lack of antibody production following immunization in old age: association with CD8(+)CD28(−) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol 168(11):5893–5899PubMedGoogle Scholar
  100. Schmitt A, Tonn T, Busch DH et al (2011) Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 51(3):591–599PubMedGoogle Scholar
  101. Schwanninger A, Weinberger B, Weiskopf D et al (2008) Age-related appearance of a CMV-specific high-avidity CD8+ T cell clonotype which does not occur in young adults. Immun Ageing 5:14PubMedGoogle Scholar
  102. Sester M, Sester U, Gartner B et al (2002) Sustained high frequencies of specific CD4+ T cells restricted to a single persistent virus. J Virol 76(8):3748–3755PubMedGoogle Scholar
  103. Sinicco A, Raiteri R, Sciandra M et al (1997) The influence of cytomegalovirus on the natural history of HIV infection: evidence of rapid course of HIV infection in HIV-positive patients infected with cytomegalovirus. Scand J Infect Dis 29(6):543–549PubMedGoogle Scholar
  104. Smithey MJ, Renkema KR, Rudd BD et al (2011) Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur J Immunol 41(5):1352–1364PubMedGoogle Scholar
  105. Smithey MJ, Li G, Venturi V et al (2012) Lifelong persistent viral infection alters the naive T cell pool, impairing CD8+ T cell immunity in late life. J Immunol 189(11):5356–5366PubMedGoogle Scholar
  106. Snyder CM, Cho KS, Bonnett EL et al (2008) Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29(4):650–659PubMedGoogle Scholar
  107. Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24(5):491–494PubMedGoogle Scholar
  108. Strindhall J, Nilsson BO, Lofgren S et al (2007) No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42(8):753–761PubMedGoogle Scholar
  109. Sylwester AW, Mitchell BL, Edgar JB et al (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202(5):673–685PubMedGoogle Scholar
  110. Tatum A, Hill AB (2012) Chronic viral infections and immunosenescence, with a focus on CMV. Open Longevity Science 6:33–38Google Scholar
  111. Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93PubMedGoogle Scholar
  112. Trautmann L, Rimbert M, Echasserieau K et al (2005) Selection of T cell clones expressing high-affinity public TCRs within Human cytomegalovirus-specific CD8+ T cell responses. J Immunol 175(9):6123–6132PubMedGoogle Scholar
  113. Trzonkowski P, Mysliwska J, Szmit E et al (2003) Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination–an impact of immunosenescence. Vaccine 21(25–26):3826–3836PubMedGoogle Scholar
  114. Valkenburg SA, Venturi V, Dang TH et al (2012) Early priming minimizes the age-related immune compromise of CD8(+) T cell diversity and function. PLoS Pathog 8(2):e1002544PubMedGoogle Scholar
  115. van den Holland AM, Brink MR (2009) Rejuvenation of the aging T cell compartment. Curr Opin Immunol 21(4):454–459PubMedGoogle Scholar
  116. Van Waterstrat A, Zant G (2009) Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol 21(4):408–413PubMedGoogle Scholar
  117. Varani S, Frascaroli G, Landini MP et al (2009) Human cytomegalovirus targets different subsets of antigen-presenting cells with pathological consequences for host immunity: implications for immunosuppression, chronic inflammation and autoimmunity. Rev Med Virol 19(3):131–145PubMedGoogle Scholar
  118. Vescovini R, Telera A, Fagnoni FF et al (2004) Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 39(8):1233–1243PubMedGoogle Scholar
  119. Vezys V, Yates A, Casey KA et al (2008) Memory CD8+ T-cell compartment grows in size with immunological experience. Nature 457(7226):196–199PubMedGoogle Scholar
  120. Vu T, Farish S, Jenkins M et al (2002) A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community. Vaccine 20(13–14):1831–1836PubMedGoogle Scholar
  121. Waller EC, Day E, Sissons JG et al (2008) Dynamics of T cell memory in human cytomegalovirus infection. Med Microbiol Immunol 197(2):83–96PubMedGoogle Scholar
  122. Wikby A, Maxson P, Olsson J et al (1998) Changes in CD8+ and CD4+ lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev 102(2–3):187–198PubMedGoogle Scholar
  123. Wikby A, Johansson B, Olsson J et al (2002) Expansions of peripheral blood CD8+ T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 37(2–3):445–453PubMedGoogle Scholar
  124. Xie D, McElhaney JE (2007) Lower GrB + CD62Lhigh CD8+ TCM effector lymphocyte response to influenza virus in older adults is associated with increased CD28null CD8+ T lymphocytes. Mech Ageing Dev 128(5–6):392–400PubMedGoogle Scholar
  125. Yager EJ, Ahmed M, Lanzer K et al (2008) Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 205(3):711–723PubMedGoogle Scholar
  126. Yewdell JW, Haeryfar SM (2005) Understanding presentation of viral antigens to CD8(+) T cells in vivo: the key to rational vaccine design. Annu Rev Immunol 23:651–682PubMedGoogle Scholar
  127. Zhu Q, Egelston C, Gagnon S et al (2010) Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J Clin Invest 120(2):607–616PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Trudeau InstituteSaranac LakeUSA
  2. 2.Keystone SymposiaSilverthorneUSA

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