Age-Specific T Cell Homeostasis

  • Christine Bourgeois
  • Delphine SauceEmail author
Living reference work entry


Multiples defects affect adaptive immunity during aging: T cell production (both at thymic and peripheral sites), T cell activation (including TCR sensitivity, proliferation, and differentiation), T cell functions, and T cell survival. Most of these defects directly impact T cell homeostasis. Indeed T cell homeostasis refers to the maintenance of steady state in the body and the physiological processes through which they are regulated. This mechanism ensures a close equilibrium between T cell production and death, two aspects that are drastically affected during aging.

The aim of this chapter is to review the changes in T cell homeostasis developing during aging. We will first review the main homeostatic mechanisms that have been described so far in adult individuals. In a second part, we will document the age-related events that crucially impact T cell homeostasis and the resulting effects on peripheral T cell pools. Finally, the potential benefits of regenerative therapies aiming to restore T cell homeostasis will be discussed.


T lymphocytes Viral infection Aging IL-7 CD8 expansion 





Hematopoietic stem cells




T cell repertoire


Thymic epithelial cell


  1. Adorini L, Penna G, Giarratana N, Uskokovic M (2003) Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J Cell Biochem 88(2):227–233PubMedCrossRefPubMedCentralGoogle Scholar
  2. Akbar AN, Henson SM (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11(4):289–295PubMedCrossRefPubMedCentralGoogle Scholar
  3. Anderson G, Jenkinson EJ (2001) Lymphostromal interactions in thymic development and function. Nat Rev Immunol 1(1):31–40PubMedCrossRefPubMedCentralGoogle Scholar
  4. 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):379–385PubMedCrossRefPubMedCentralGoogle Scholar
  5. Aspinall R (2006) T cell development, ageing and Interleukin-7. Mech Ageing Dev 127(6):572–578PubMedCrossRefPubMedCentralGoogle Scholar
  6. Aspinall R, Andrew D (2000) Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine 18(16):1629–1637PubMedCrossRefPubMedCentralGoogle Scholar
  7. Aw D, Palmer DB (2011) The origin and implication of thymic involution. Aging Dis 2(5):437–443PubMedPubMedCentralGoogle Scholar
  8. Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB (2008) Architectural changes in the thymus of aging mice. Aging Cell 7(2):158–167PubMedCrossRefPubMedCentralGoogle Scholar
  9. Babizhayev MA, Vishnyakova KS, Yegorov YE (2014) Oxidative damage impact on aging and age-related diseases: drug targeting of telomere attrition and dynamic telomerase activity flirting with imidazole-containing dipeptides. Recent Pat Drug Deliv Formul 8(3):163–192PubMedCrossRefPubMedCentralGoogle Scholar
  10. Becker TC, Wherry EJ, Boone D et al (2002) Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 195(12):1541–1548PubMedPubMedCentralCrossRefGoogle Scholar
  11. Becker TC, Coley SM, Wherry EJ, Ahmed R (2005) Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J Immunol (Baltimore, Md: 1950) 174(3):1269–1273CrossRefGoogle Scholar
  12. Beerman I, Maloney WJ, Weissmann IL, Rossi DJ (2010) Stem cells and the aging hematopoietic system. Curr Opin Immunol 22(4):500–506PubMedPubMedCentralCrossRefGoogle Scholar
  13. Berger R, Florent G (1981) Just M. Decrease of the lymphoproliferative response to varicella-zoster virus antigen in the aged. Infect Immun 32(1):24–27PubMedPubMedCentralGoogle Scholar
  14. Berstein LM, Tsyrlina EV, Vasilyev DA, Poroshina TE, Kovalenko RG (2005) The phenomenon of the switching of estrogen effects and joker function of glucose: similarities and relation to age-associated pathology and approaches to correction. Ann NY Acad Sci 1057:235–246PubMedCrossRefPubMedCentralGoogle Scholar
  15. Bertho JM, Demarquay C, Moulian N, Van Der Meeren A, Berrih-Aknin S, Gourmelon P (1997) Phenotypic and immunohistological analyses of the human adult thymus: evidence for an active thymus during adult life. Cell Immunol 179(1):30–40PubMedCrossRefPubMedCentralGoogle Scholar
  16. Berzins SP, Boyd RL, Miller JF (1998) The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J Exp Med 187(11):1839–1848PubMedPubMedCentralCrossRefGoogle Scholar
  17. Beura LK, Hamilton SE, Bi K et al (2016) Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532(7600):512–516PubMedPubMedCentralCrossRefGoogle Scholar
  18. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P (2012) Aging of the human metaorganism: the microbial counterpart. Age (Dordr) 34(1):247–267CrossRefGoogle Scholar
  19. Blattman JN, Antia R, Sourdive DJD et al (2002) Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 195(5):657–664PubMedPubMedCentralCrossRefGoogle Scholar
  20. Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 103(20):7901–7905PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bourgeois C, Kassiotis G, Stockinger B (2005) A major role for memory CD4 T cells in the control of lymphopenia-induced proliferation of naive CD4 T cells. J Immunol 174(9):5316–5323PubMedCrossRefPubMedCentralGoogle Scholar
  22. Bourgeois C, Hao Z, Rajewsky K, Potocnik AJ, Stockinger B (2008) Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci USA 105(25):8691–8696PubMedPubMedCentralCrossRefGoogle Scholar
  23. Brenchley JM, Price DA, Schacker TW et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12(12):1365–1371PubMedCrossRefPubMedCentralGoogle Scholar
  24. Buford TW, Willoughby DS (2008) Impact of DHEA(S) and cortisol on immune function in aging: a brief review. Appl Physiol Nutr Metab 33(3):429–433PubMedCrossRefPubMedCentralGoogle Scholar
  25. Butcher SK, Killampalli V, Lascelles D, Wang K, Alpar EK, Lord JM (2005) Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell 4(6):319–324PubMedCrossRefPubMedCentralGoogle Scholar
  26. Chaix J, Nish SA, Lin W-HW et al (2014) Cutting edge: CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal. J Immunol (Baltimore, Md: 1950) 193(3):1013–1016CrossRefGoogle Scholar
  27. Chinn IK, Blackburn CC, Manley NR, Sempowski GD (2012) Changes in primary lymphoid organs with aging. Semin Immunol 24(5):309–320PubMedPubMedCentralCrossRefGoogle Scholar
  28. 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 USA 104:19960–19965PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cicin-Sain L, Smyk-Pearson S, Smyk-Paerson S et al (2010) Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J Immunol (Baltimore, Md: 1950) 184(12):6739–6745CrossRefGoogle Scholar
  30. Cosgrove D, Gray D, Ae D et al (1991) Mice lacking MHC class II molecules. Cell 66(5):1051–1066PubMedCrossRefPubMedCentralGoogle Scholar
  31. De Riva A, Bourgeois C, Kassiotis G, Stockinger B (2007) Noncognate interaction with MHC class II molecules is essential for maintenance of T cell metabolism to establish optimal memory CD4 T cell function. J Immunol 178(9):5488–5495PubMedCrossRefPubMedCentralGoogle Scholar
  32. 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):288–297CrossRefGoogle Scholar
  33. Di Mascio M, Paik CH, Carrasquillo JA et al (2009) Noninvasive in vivo imaging of CD4 cells in simian-human immunodeficiency virus (SHIV)-infected nonhuman primates. Blood 114(2):328–337PubMedPubMedCentralCrossRefGoogle Scholar
  34. Di Rosa F (2016) Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation? Nat Rev Immunol 16(4):271PubMedCrossRefPubMedCentralGoogle Scholar
  35. Dixit VD (2010) Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr Opin Immunol 22(4):521–528PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dixit VD, Yang H, Sun Y et al (2007) Ghrelin promotes thymopoiesis during aging. J Clin Invest 117(10):2778PubMedPubMedCentralCrossRefGoogle Scholar
  37. Dudakov JA, Hanash AM, Jenq RR et al (2012) Interleukin-22 drives endogenous thymic regeneration in mice. Science 336(6077):91–95PubMedPubMedCentralCrossRefGoogle Scholar
  38. Effros RB (2004) Replicative senescence of CD8 T cells: effect on human ageing. Exp Gerontol 39(4):517–524PubMedCrossRefPubMedCentralGoogle Scholar
  39. Fabre-Mersseman V, Tubiana R, Papagno L et al (2014) Vitamin D supplementation is associated with reduced immune activation levels in HIV-1-infected patients on suppressive antiretroviral therapy. AIDS 28(18):2677–2682PubMedCrossRefPubMedCentralGoogle Scholar
  40. Fagnoni FF, Vescovini R, Passeri G et al (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95(9):2860–2868PubMedPubMedCentralGoogle Scholar
  41. Fink PJ (2013) The biology of recent thymic emigrants. Annu Rev Immunol 31:31–50PubMedCrossRefPubMedCentralGoogle Scholar
  42. Flach J, Bakker ST, Mohrin M et al (2014) Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512(7513):198–202PubMedPubMedCentralCrossRefGoogle Scholar
  43. Fletcher JM, Vukmanovic-Stejic M, Dunne PJ et al (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175(12):8218–8225PubMedCrossRefPubMedCentralGoogle Scholar
  44. Foody JM, Shah R, Galusha D, Masoudi FA, Havranek EP, Krumholz HM (2006) Statins and mortality among elderly patients hospitalized with heart failure. Circulation 113(8):1086–1092PubMedCrossRefPubMedCentralGoogle Scholar
  45. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–S9PubMedCrossRefPubMedCentralGoogle Scholar
  46. Franceschi C, Capri M, Monti D et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105PubMedCrossRefPubMedCentralGoogle Scholar
  47. Freitas AA, Rocha BB (1993) Lymphocyte lifespans: homeostasis, selection and competition. Immunol Today 14(1):25–29PubMedCrossRefPubMedCentralGoogle Scholar
  48. French RA, Broussard SR, Meier WA et al (2002) Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology 143(2):690–699PubMedCrossRefPubMedCentralGoogle Scholar
  49. Fry TJ, Mackall CL (2001) Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol 22(10):564–571PubMedCrossRefPubMedCentralGoogle Scholar
  50. Fung-Leung W-P, Schilham MW, Rahemtulla A et al (1991) CD8 is needed for development of cytotoxic T but not helper T cells. Cell 65(3):443–449PubMedCrossRefPubMedCentralGoogle Scholar
  51. Gabor MJ, Scollay R, Godfrey DI (1997) Thymic T cell export is not influenced by the peripheral T cell pool. Eur J Immunol 27(11):2986–2993PubMedCrossRefPubMedCentralGoogle Scholar
  52. Ganusov VV, De Boer RJ (2007) Do most lymphocytes in humans really reside in the gut? Trends Immunol 28(12):514–518PubMedCrossRefPubMedCentralGoogle Scholar
  53. Ganusov VV, De Boer RJ (2008) Tissue distribution of lymphocytes and plasma cells and the role of the gut: response to Pabst et al. Trends Immunol 29:209–210CrossRefGoogle Scholar
  54. Garrod KR, Moreau HD, Garcia Z et al (2012) Dissecting T cell contraction in vivo using a genetically encoded reporter of apoptosis. Cell Rep 2(5):1438–1447PubMedCrossRefPubMedCentralGoogle Scholar
  55. Gattinoni L, Lugli E, Ji Y et al (2011) A human memory T cell subset with stem cell-like properties. Nat Med 17(10):1290–1297PubMedPubMedCentralCrossRefGoogle Scholar
  56. Ge Q, Hu H, Eisen HN, Chen J (2002) Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments. Proc Natl Acad Sci USA 99(5):2989–2994PubMedPubMedCentralCrossRefGoogle Scholar
  57. Geiger H, de Haan G, Florian MC (2013) The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13(5):376–389PubMedCrossRefPubMedCentralGoogle Scholar
  58. Goronzy JJ, Weyand CM (2013) Understanding immunosenescence to improve responses to vaccines. Nat Immunol 14(5):428–436PubMedPubMedCentralCrossRefGoogle Scholar
  59. Gray DH, Seach N, Ueno T et al (2006) Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108(12):3777–3785PubMedCrossRefPubMedCentralGoogle Scholar
  60. Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211(2):144–156PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM (2007) The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol 19(10):1201–1211PubMedCrossRefPubMedCentralGoogle Scholar
  62. Guimond M, Fry TJ, Mackall CL (2005) Cytokine signals in T-cell homeostasis. J Immunother 28(4):289–294PubMedCrossRefPubMedCentralGoogle Scholar
  63. Guimond M, Veenstra RG, Grindler DJ et al (2009) Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol 10(2):149–157PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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):2645–2653PubMedCrossRefPubMedCentralGoogle Scholar
  65. Haines CJ, Giffon TD, Lu L-S et al (2009) Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J Exp Med 206(2):275–285PubMedPubMedCentralCrossRefGoogle Scholar
  66. Harley CB, Liu W, Blasco M et al (2010) A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res 14(1):45–56PubMedCrossRefPubMedCentralGoogle Scholar
  67. Hassan J, Reen DJ (2001) Human recent thymic emigrants – identification, expansion, and survival characteristics. J Immunol (Baltimore, Md: 1950) 167(4):1970–1976CrossRefGoogle Scholar
  68. Hong C, Luckey MA, Park JH (2012) Intrathymic IL-7: the where, when, and why of IL-7 signaling during T cell development. Semin Immunol 24(3):151–158PubMedPubMedCentralCrossRefGoogle Scholar
  69. Houston EG, Higdon LE, Fink PJ (2011) Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool. Proc Natl Acad Sci USA 108(13):5366–5371PubMedPubMedCentralCrossRefGoogle Scholar
  70. Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2(8):547–556PubMedCrossRefPubMedCentralGoogle Scholar
  71. Jameson SC (2005) T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin Immunol 17(3):231–237PubMedCrossRefPubMedCentralGoogle Scholar
  72. Jurk D, Wilson C, Passos JF et al (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2:4172PubMedPubMedCentralCrossRefGoogle Scholar
  73. 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):7481–7489PubMedCrossRefPubMedCentralGoogle Scholar
  74. Kim HK, Waickman AT, Castro E et al (2016) Distinct IL-7 signaling in recent thymic emigrants versus mature naïve T cells controls T-cell homeostasis. Eur J Immunol 46:1669PubMedCrossRefPubMedCentralGoogle Scholar
  75. Kitamura D, Roes J, Kühn R, Rajewsky K (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350(6317):423–426PubMedCrossRefPubMedCentralGoogle Scholar
  76. Klonowski KD, Williams KJ, Marzo AL, Blair DA, Lingenheld EG, Lefrancois L (2004) Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20(5):551–562PubMedCrossRefPubMedCentralGoogle Scholar
  77. Kohler S, Thiel A (2009) Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood 113(4):769–774PubMedCrossRefPubMedCentralGoogle Scholar
  78. Kovacs EJ (2005) Aging, traumatic injury, and estrogen treatment. Exp Gerontol 40(7):549–555PubMedCrossRefPubMedCentralGoogle Scholar
  79. 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):2186–2193PubMedCrossRefPubMedCentralGoogle Scholar
  80. LeMaoult J, Messaoudi I, Manavalan JS et al (2000) Age-related dysregulation in CD8 T cell homeostasis: kinetics of a diversity loss. J Immunol (Baltimore, Md: 1950) 165(5):2367–2373CrossRefGoogle Scholar
  81. Lesourd BM (1997) Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. Am J Clin Nutr 66(2):478S–484SPubMedCrossRefPubMedCentralGoogle Scholar
  82. Levin MJ, Schmader KE, Pang L et al (2016) Cellular and humoral responses to a second dose of herpes zoster vaccine administered 10 years after the first dose among older adults. J Infect Dis 213(1):14–22PubMedCrossRefPubMedCentralGoogle Scholar
  83. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5(2):133–139PubMedCrossRefPubMedCentralGoogle Scholar
  84. Lucas M, Vargas-Cuero AL, Lauer GM et al (2004) Pervasive influence of hepatitis C virus on the phenotype of antiviral CD8+ T cells. J Immunol 172(3):1744–1753PubMedCrossRefPubMedCentralGoogle Scholar
  85. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MR, Boyd R, Sempowski GD (2009) Thymic involution and immune reconstitution. Trends Immunol 30(7):366–373PubMedPubMedCentralCrossRefGoogle Scholar
  86. Maczek C, Berger TG, Schuler-Thurner B et al (2005) Differences in phenotype and function between spontaneously occurring melan-A-, tyrosinase- and influenza matrix peptide-specific CTL in HLA-A*0201 melanoma patients. Int J Cancer 115(3):450–455PubMedCrossRefPubMedCentralGoogle Scholar
  87. Malissen M, Gillet A, Ardouin L et al (1995) Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J 14(19):4641–4653PubMedPubMedCentralCrossRefGoogle Scholar
  88. Markert ML, Boeck A, Hale LP et al (1999) Transplantation of thymus tissue in complete DiGeorge syndrome. N Engl J Med 341(16):1180–1189PubMedCrossRefPubMedCentralGoogle Scholar
  89. Martinet KZ, Bloquet S, Bourgeois C (2014) Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue. Immun Ageing 11:8PubMedPubMedCentralCrossRefGoogle Scholar
  90. Mazo IB, Honczarenko M, Leung H et al (2005) Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 22(2):259–270PubMedCrossRefPubMedCentralGoogle Scholar
  91. Mazzucchelli R, Durum SK (2007) Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 7(2):144–154PubMedCrossRefPubMedCentralGoogle Scholar
  92. McKerrell T, Park N, Moreno T et al (2015) Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 10(8):1239–1245PubMedPubMedCentralCrossRefGoogle Scholar
  93. Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J (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):1347–1358PubMedPubMedCentralCrossRefGoogle Scholar
  94. Messaoudi I, Warner J, Nikolich-Zugich J (2006) 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):2784–2792PubMedCrossRefPubMedCentralGoogle Scholar
  95. Min B, Foucras G, Meier-Schellersheim M, Paul WE (2004) Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci USA 101(11):3874–3879PubMedPubMedCentralCrossRefGoogle Scholar
  96. Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109(6):2529–2537PubMedPubMedCentralCrossRefGoogle Scholar
  97. Mitchell WA, Lang PO, Aspinall R (2010) Tracing thymic output in older individuals. Clin Exp Immunol 161(3):497–503PubMedPubMedCentralCrossRefGoogle Scholar
  98. Montecino-Rodriquez E, Min H, Dorshkind K (2005) Reevaluating current models of thymic involution. Semin Immunol 17(5):356–361PubMedCrossRefPubMedCentralGoogle Scholar
  99. Mueller SN, Gebhardt T, Carbone FR, Heath WR (2013) Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol 31:137–161PubMedCrossRefPubMedCentralGoogle Scholar
  100. Murali-Krishna K, Ahmed R (2000) Cutting edge: naive T cells masquerading as memory cells. J Immunol (Baltimore, Md: 1950) 165(4):1733–1737CrossRefGoogle Scholar
  101. Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8(7):512–522PubMedPubMedCentralCrossRefGoogle Scholar
  102. Oehen S, Brduscha-Riem K (1999) Naive cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies? Eur J Immunol 29(2):608–614PubMedCrossRefPubMedCentralGoogle Scholar
  103. Ogra PL (2010) Ageing and its possible impact on mucosal immune responses. Ageing Res Rev 9(2):101–106PubMedCrossRefPubMedCentralGoogle Scholar
  104. Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121(1–3):187–201PubMedPubMedCentralGoogle Scholar
  105. Opiela SJ, Koru-Sengul T, Adkins B (2009) Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants. Blood 113(22):5635–5643PubMedPubMedCentralCrossRefGoogle Scholar
  106. O'Toole PW, Jeffery IB (2015) Gut microbiota and aging. Science 350(6265):1214–1215PubMedCrossRefPubMedCentralGoogle Scholar
  107. Oxman MN, Levin MJ, Johnson GR et al (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352(22):2271–2284PubMedCrossRefPubMedCentralGoogle Scholar
  108. Palmer MJ, Mahajan VS, Chen J, Irvine DJ, Lauffenburger DA (2011) Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naïve CD8(+) T cells. Immunol Cell Biol 89(5):581–594PubMedPubMedCentralCrossRefGoogle Scholar
  109. Passtoors WM, van den Akker EB, Deelen J et al (2015) IL7R gene expression network associates with human healthy ageing. Immun Ageing 12:21PubMedPubMedCentralCrossRefGoogle Scholar
  110. Pawelec G, Akbar A, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A (2004) Is immunosenescence infectious? Trends Immunol 25(8):406–410PubMedCrossRefPubMedCentralGoogle Scholar
  111. Posnett DN, Sinha R, Kabak S, Russo C (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J Exp Med 179(2):609–618PubMedCrossRefPubMedCentralGoogle Scholar
  112. Preza GC, Yang OO, Elliott J, Anton PA, Ochoa MT (2015) T lymphocyte density and distribution in human colorectal mucosa, and inefficiency of current cell isolation protocols. PLoS One 10(4):e0122723PubMedPubMedCentralCrossRefGoogle Scholar
  113. Pulko V, Davies JS, Martinez C et al (2016) Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat Immunol 17:966PubMedPubMedCentralCrossRefGoogle Scholar
  114. Qi Q, Zhang DW, Weyand CM, Goronzy J Jr (2014a) Mechanisms shaping the naïve T cell repertoire in the elderly – Thymic involution or peripheral homeostatic proliferation? Exp Gerontol 54:71–74PubMedPubMedCentralCrossRefGoogle Scholar
  115. Qi Q, Liu Y, Cheng Y et al (2014b) Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci USA 111(36):13139–13144PubMedPubMedCentralCrossRefGoogle Scholar
  116. Rahemtulla A, Fung-Leung WP, Schilham MW et al (1991) Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353(6340):180–184PubMedCrossRefPubMedCentralGoogle Scholar
  117. Ravussin E, Redman LM, Rochon J et al (2015) A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J Gerontol A Biol Sci Med Sci 70(9):1097–1104PubMedPubMedCentralCrossRefGoogle Scholar
  118. Rea IM, Alexander HD, Crockard AD, Morris TC (1996) CD4 lymphopenia in very elderly people. Lancet 347(8997):328–329PubMedPubMedCentralGoogle Scholar
  119. Reynolds J, Coles M, Lythe G, Molina-París C (2013) Mathematical model of naive T cell division and survival IL-7 thresholds. Front Immunol 4:434PubMedPubMedCentralCrossRefGoogle Scholar
  120. Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9(7):480–490PubMedPubMedCentralCrossRefGoogle Scholar
  121. Saffrey MJ (2014) Aging of the mammalian gastrointestinal tract: a complex organ system. Age (Dordr) 36(3):9603CrossRefGoogle Scholar
  122. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712PubMedCrossRefPubMedCentralGoogle Scholar
  123. Sauce D, Rufer N, Mercier P et al (2003) Retrovirus-mediated gene transfer in polyclonal T cells results in lower apoptosis and enhanced ex vivo cell expansion of CMV-reactive CD8 T cells as compared with EBV-reactive CD8 T cells. Blood 102(4):1241–1248PubMedCrossRefPubMedCentralGoogle Scholar
  124. Sauce D, Larsen M, Fastenackels S et al (2009) Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest 119:3070–3078PubMedPubMedCentralCrossRefGoogle Scholar
  125. Sauce D, Larsen M, Fastenackels S et al (2012) Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults. J Immunol (Baltimore, Md: 1950) 189(12):5541–5548CrossRefGoogle Scholar
  126. Scheinfeld N (2005) Infections in the elderly. Dermatol Online J 11(3):8PubMedPubMedCentralGoogle Scholar
  127. Schenkel JM, Masopust D (2014) Tissue-resident memory T cells. Immunity 41(6):886–897PubMedPubMedCentralCrossRefGoogle Scholar
  128. Schluns KS, Kieper WC, Jameson SC, Lefrancois L (2000) Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 1(5):426–432PubMedCrossRefPubMedCentralGoogle Scholar
  129. Schmucker DL, Thoreux K, Owen RL (2001) Aging impairs intestinal immunity. Mech Ageing Dev 122(13):1397–1411PubMedCrossRefPubMedCentralGoogle Scholar
  130. Sempowski G, Thomasch J, Gooding M et al (2001) Effect of thymectomy on human peripheral blood T cell pools in myasthenia gravis. J Immunol (Baltimore, Md: 1950) 166(4):2808–2817CrossRefGoogle Scholar
  131. Seruga B, Zhang H, Bernstein LJ, Tannock IF (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8(11):887–899PubMedCrossRefPubMedCentralGoogle Scholar
  132. Sperka T, Wang J, Rudolph KL (2012) DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13(9):579–590PubMedCrossRefPubMedCentralGoogle Scholar
  133. Steinert EM, Schenkel JM, Fraser KA et al (2015) Quantifying memory CD8 T cells reveals regionalization of Immunosurveillance. Cell 161(4):737–749PubMedPubMedCentralCrossRefGoogle Scholar
  134. Steinmann GG (1986) Changes in the human thymus during aging. Curr Top Pathol 75:43–88PubMedCrossRefPubMedCentralGoogle Scholar
  135. Stockinger B, Kassiotis G, Bourgeois C (2004) Homeostasis and T cell regulation. Curr Opin Immunol 16(6):775–779PubMedCrossRefPubMedCentralGoogle Scholar
  136. Surh CD, Sprent J (2008) Homeostasis of naive and memory T cells. Immunity 29(6):848–862PubMedCrossRefPubMedCentralGoogle Scholar
  137. Sutherland JS, Goldberg GL, Hammett MV et al (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741–2753PubMedCrossRefPubMedCentralGoogle Scholar
  138. Takeda S, Rodewald H-R, Arakawa H, Bluethmann H, Shimizu T (1996) MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity 5(3):217–228PubMedCrossRefPubMedCentralGoogle Scholar
  139. Tanchot C, Rocha B (1995) The peripheral T cell repertoire: independent homeostatic regulation of virgin and activated CD8+ T cell pools. Eur J Immunol 25(8):2127–2136PubMedCrossRefPubMedCentralGoogle Scholar
  140. Tanchot C, Rocha B (1998) The organization of mature T-cell pools. Immunol Today 19(12):575–579PubMedCrossRefPubMedCentralGoogle Scholar
  141. Tanchot C, Rosado MM, Agenes F, Freitas AA, Rocha B (1997a) Lymphocyte homeostasis. Semin Immunol 9(6):331–337PubMedCrossRefPubMedCentralGoogle Scholar
  142. Tanchot C, Lemonnier FA, Perarnau B, Freitas AA, Rocha B (1997b) Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276(5321):2057–2062PubMedCrossRefPubMedCentralGoogle Scholar
  143. Tanchot C, Le Campion A, Martin B, Léaument S, Dautigny N, Lucas B (2002) 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 (Baltimore, Md: 1950) 168(10):5042–5046CrossRefGoogle Scholar
  144. Tough DF, Sprent J (1994) Turnover of naive- and memory-phenotype T cells. J Exp Med 179(4):1127–1135PubMedCrossRefPubMedCentralGoogle Scholar
  145. Tsukahara A, Seki S, Iiai T et al (1997) Mouse liver T cells: their change with aging and in comparison with peripheral T cells. Hepatology (Baltimore, Md) 26(2):301–309CrossRefGoogle Scholar
  146. Vadasz Z, Haj T, Kessel A, Toubi E (2013) Age-related autoimmunity. BMC Med 11:94PubMedPubMedCentralCrossRefGoogle Scholar
  147. Vallejo AN (2007) Immune remodeling: lessons from repertoire alterations during chronological aging and in immune-mediated disease. Trends Mol Med 13(3):94–102PubMedCrossRefPubMedCentralGoogle Scholar
  148. van den Broek T, Delemarre EM, Janssen WJM et al (2016) Neonatal thymectomy reveals differentiation and plasticity within human naive T cells. J Clin Invest 126(3):1126–1136PubMedPubMedCentralCrossRefGoogle Scholar
  149. Van Zant G, Liang Y (2012) Concise review: hematopoietic stem cell aging, life span, and transplantation. Stem Cells Transl Med 1(9):651–657PubMedPubMedCentralCrossRefGoogle Scholar
  150. Veiga-Fernandes H, Walter U, Bourgeois C, McLean A, Rocha B (2000) Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nat Immunol 1(1):47–53PubMedCrossRefPubMedCentralGoogle Scholar
  151. Weekes MP, Carmichael AJ, Wills MR, Mynard K, Sissons JG (1999) Human CD28-CD8+ T cells contain greatly expanded functional virus-specific memory CTL clones. J Immunol 162(12):7569–7577PubMedPubMedCentralGoogle Scholar
  152. Wertheimer AM, Bennett MS, Park B et al (2014) Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J Immunol (Baltimore, Md: 1950) 192(5):2143–2155CrossRefGoogle Scholar
  153. Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F (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):445–453PubMedCrossRefPubMedCentralGoogle Scholar
  154. Yahata T, Takanashi T, Muguruma Y et al (2011) Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood 118(11):2941–2950PubMedCrossRefPubMedCentralGoogle Scholar
  155. Yang H, Youm YH, Dixit VD (2009) Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J Immunol 183(5):3040–3052PubMedPubMedCentralCrossRefGoogle Scholar
  156. Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su DM (2007) Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell 6(5):663–672PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.INSERM U1184, Centre d’Immunologie des maladies virales et auto-immunes (IMVA)Université Paris SUDLe Kremlin-BicêtreFrance
  2. 2.INSERM, U1135, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris)Sorbonne UniversitésParisFrance

Personalised recommendations