Advertisement

Journal of Clinical Immunology

, Volume 31, Issue 2, pp 137–146 | Cite as

Gain and Loss of T Cell Subsets in Old Age—Age-Related Reshaping of the T Cell Repertoire

  • Christoph R. Arnold
  • Juliane Wolf
  • Stefan Brunner
  • Dietmar Herndler-Brandstetter
  • Beatrix Grubeck-LoebensteinEmail author
Article

Abstract

The immune system is affected by the aging process and undergoes significant age-related changes, termed immunosenescence. Different T cell subsets are affected by this process. Alterations within the bone marrow and thymus lead to a shift in the composition of the T cell repertoire from naïve to antigen-experienced T cells, thereby compromising the diversity of the T cell pool. Additional infection with latent pathogens such as cytomegalovirus aggravates this process. In this review, we focus on the major age-related changes that occur in the naïve and the antigen-experienced T cell population. We discuss the mechanisms responsible for the generation and maintenance of these subsets and how age-related changes can be delayed or prevented by clinical interventions.

Keywords

Immunosenescence T cells aging human 

References

  1. 1.
    Grubeck-Loebenstein B, Berger P, Saurwein-Teissl M, Zisterer K, Wick G. No immunity for the elderly. Nat Med. 1998;4(8):870.PubMedCrossRefGoogle Scholar
  2. 2.
    Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis. 2008;46(7):1078–84.PubMedCrossRefGoogle Scholar
  3. 3.
    Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. 2007;25(16):3066–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5(2):133–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Gupta S, Su H, Bi R, Agrawal S, Gollapudi S. Life and death of lymphocytes: a role in immunesenescence. Immun Ageing. 2005;2:12.PubMedCrossRefGoogle Scholar
  6. 6.
    Brunner S, Herndler-Brandstetter D, Weinberger B and Grubeck-Loebenstein B: Persistent viral infections and immune aging. Ageing Res Rev. 2010 (in press)Google Scholar
  7. 7.
    Kohler S, Thiel A. Life after the thymus: CD31+ and CD31− human naïve CD4+ T-cell subsets. Blood. 2009;113(4):769–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396(6712):690–5.PubMedGoogle Scholar
  9. 9.
    Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Natural. 2007;447(7145):725–9.CrossRefGoogle Scholar
  10. 10.
    Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13(6):742–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Wagner W, Horn P, Bork S, Ho AD. Aging of hematopoietic stem cells is regulated by the stem cell niche. Exp Gerontol. 2008;43(11):974–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Steinmann GG. Changes in the human thymus during aging. Curr Top Pathol. 1986;75:43–88.PubMedGoogle Scholar
  13. 13.
    George AJ, Ritter MA. Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today. 1996;17(6):267–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Aspinall R, Andrew D. Thymic involution in aging. J Clin Immunol. 2000;20(4):250–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, et al. Shortage of circulating naïve CD8(+) T cells provides new insights on immunodeficiency in aging. Blood. 2000;95(9):2860–8.PubMedGoogle Scholar
  16. 16.
    Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, Grubeck-Loebenstein B. Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology. 2005;114(1):37–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Prelog M, Keller M, Geiger R, Brandstatter A, Wurzner R, Schweigmann U, et al. Thymectomy in early childhood: significant alterations of the CD4(+)CD45RA(+)CD62L(+) T cell compartment in later life. Clin Immunol. 2009;130(2):123–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebenstein B, et al. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest. 2009;119(10):3070–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Swain S, Clise-Dwyer K, Haynes L. Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol. 2005;17(5):370–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, et al. Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly. Hum Immunol. 2007;68(2):86–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Effros RB, Cai Z, Linton PJ. CD8 T cells and aging. Crit Rev Immunol. 2003;23(1–2):45–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Pfister G, Weiskopf D, Lazuardi L, Kovaiou RD, Cioca DP, Keller M, et al. Naïve T cells in the elderly: are they still there? Ann NY Acad Sci. 2006;1067:152–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007;42(5):400–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174(11):7446–52.PubMedGoogle Scholar
  25. 25.
    Gupta S, Gollapudi S. TNF-alpha-induced apoptosis in human naïve and memory CD8+ T cells in aged humans. Exp Gerontol. 2006;41(1):69–77.PubMedCrossRefGoogle Scholar
  26. 26.
    Gupta S, Gollapudi S. CD95-mediated apoptosis in naïve, central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol. 2008;43(4):266–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2000;1(5):426–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Boursalian TE, Bottomly K. Survival of naïve CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu. J Immunol. 1999;162(7):3795–801.PubMedGoogle Scholar
  29. 29.
    Caserta S, Zamoyska R. Memories are made of this: synergy of T cell receptor and cytokine signals in CD4(+) central memory cell survival. Trends Immunol. 2007;28(6):245–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, et al. IL-7 is critical for homeostatic proliferation and survival of naïve T cells. Proc Natl Acad Sci USA. 2001;98(15):8732–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Barnett YA, Barnett CR. DNA damage and mutation: contributors to the age-related alterations in T cell-mediated immune responses? Mech Ageing Dev. 1998;102(2–3):165–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, et al. Homeostasis of the naïve CD4+T cell compartment during aging. J Immunol. 2008;180(3):1499–507.PubMedGoogle Scholar
  33. 33.
    Cicin-Sain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, et al. Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates. Proc Natl Acad Sci USA. 2007;104(50):19960–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Mowes B, et al. Post-thymic in vivo proliferation of naïve CD4+T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005;35(6):1987–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Alves NL, Hooibrink B, Arosa FA, van Lier RA. IL-15 induces antigen-independent expansion and differentiation of human naïve CD8+T cells in vitro. Blood. 2003;102(7):2541–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Pfister G, Savino W. Can the immune system still be efficient in the elderly? An immunological and immunoendocrine therapeutic perspective. Neuroimmunomodulation. 2008;15(4–6):351–64.PubMedCrossRefGoogle Scholar
  37. 37.
    Pawelec G, Akbar A, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A. Is immunosenescence infectious? Trends Immunol. 2004;25(8):406–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Ahmed M, Lanzer KG, Yager EJ, Adams PS, Johnson LL, Blackman MA. Clonal expansions and loss of receptor diversity in the naïve CD8 T cell repertoire of aged mice. J Immunol. 2009;182(2):784–92.PubMedGoogle Scholar
  39. 39.
    Haynes L, Eaton SM. The effect of age on the cognate function of CD4+ T cells. Immunol Rev. 2005;205:220–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Haynes L, Linton PJ, Eaton SM, Tonkonogy SL, Swain SL. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naïve T cells of aged mice. J Exp Med. 1999;190(7):1013–24.PubMedCrossRefGoogle Scholar
  41. 41.
    Linton PJ, Haynes L, Klinman NR, Swain SL. Antigen-independent changes in naïve CD4 T cells with aging. J Exp Med. 1996;184(5):1891–900.PubMedCrossRefGoogle Scholar
  42. 42.
    Garcia GG, Miller RA. Age-dependent defects in TCR-triggered cytoskeletal rearrangement in CD4+ T cells. J Immunol. 2002;169(9):5021–7.PubMedGoogle Scholar
  43. 43.
    Huber LA, Xu QB, Jurgens G, Bock G, Buhler E, Gey KF, et al. Correlation of lymphocyte lipid composition membrane microviscosity and mitogen response in the aged. Eur J Immunol. 1991;21(11):2761–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Stulnig TM, Buhler E, Bock G, Kirchebner C, Schonitzer D, Wick G. Altered switch in lipid composition during T-cell blast transformation in the healthy elderly. J Gerontol A Biol Sci Med Sci. 1995;50(6):383–90.Google Scholar
  45. 45.
    Garcia GG, Miller RA. Age-related defects in CD4+ T cell activation reversed by glycoprotein endopeptidase. Eur J Immunol. 2003;33(12):3464–72.PubMedCrossRefGoogle Scholar
  46. 46.
    Miller RA, Garcia G, Kirk CJ, Witkowski JM. Early activation defects in T lymphocytes from aged mice. Immunol Rev. 1997;160:79–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Kirk CJ, Freilich AM, Miller RA. Age-related decline in activation of JNK by TCR- and CD28-mediated signals in murine T-lymphocytes. Cell Immunol. 1999;197(2):75–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Kirk CJ, Miller RA. Analysis of Raf-1 activation in response to TCR activation and costimulation in murine T-lymphocytes: effect of age. Cell Immunol. 1998;190(1):33–42.PubMedCrossRefGoogle Scholar
  49. 49.
    Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med. 2004;200(12):1613–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Haynes L, Maue AC. Effects of aging on T cell function. Curr Opin Immunol. 2009;21(4):414–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9.PubMedGoogle Scholar
  52. 52.
    Atkuri KR, Herzenberg LA, Niemi AK, Cowan T. Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci USA. 2007;104(11):4547–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Larbi A, Cabreiro F, Zelba H, Marthandan S, Combet E, Friguet B, et al. Reduced oxygen tension results in reduced human T cell proliferation and increased intracellular oxidative damage and susceptibility to apoptosis upon activation. Free Radic Biol Med. 2010;48(1):26–34.PubMedCrossRefGoogle Scholar
  54. 54.
    Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003;4(9):835–42.PubMedCrossRefGoogle Scholar
  55. 55.
    Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007;315(5819):1687–91.PubMedCrossRefGoogle Scholar
  56. 56.
    Surh CD, Sprent J. Regulation of naïve and memory T-cell homeostasis. Microbes Infect. 2002;4(1):51–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Ge Q, Hu H, Eisen HN, Chen J. Naïve to memory T-cell differentiation during homeostasis-driven proliferation. Microbes Infect. 2002;4(5):555–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 2006;7(5):475–81.PubMedCrossRefGoogle Scholar
  59. 59.
    Herndler-Brandstetter D, Veel E, Laschober GT, Pfister G, Brunner S, Walcher S, et al. Non-regulatory CD8+CD45RO+CD25+ T-lymphocytes may compensate for the loss of antigen-inexperienced CD8+CD45RA+T-cells in old age. Biol Chem. 2008;389(5):561–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Karrer U, Sierro S, Wagner M, Oxenius A, Hengel H, Koszinowski UH, et al. Memory inflation: continuous accumulation of antiviral CD8+T cells over time. J Immunol. 2003;170(4):2022–9.PubMedGoogle Scholar
  61. 61.
    Snyder CM, Cho KS, Bonnett EL, van Dommelen S, Shellam GR, Hill AB. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity. 2008;29(4):650–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M. Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment. Mech Ageing Dev. 2006;127(3):274–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Schwaiger S, Wolf AM, Robatscher P, Jenewein B, Grubeck-Loebenstein B. IL-4-producing CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age. J Immunol. 2003;170(1):613–9.PubMedGoogle Scholar
  64. 64.
    Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. CD4 T cell memory derived from young naïve cells functions well into old age, but memory generated from aged naïve cells functions poorly. Proc Natl Acad Sci USA. 2003;100(25):15053–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Tokoyoda K, Hauser AE, Nakayama T, Radbruch A. Organization of immunological memory by bone marrow stroma. Nat Rev Immunol. 2010;10(3):193–200.PubMedCrossRefGoogle Scholar
  67. 67.
    Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol. 2001;75(12):5550–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Pantaleo G, Soudeyns H, Demarest JF, Vaccarezza M, Graziosi C, Paolucci S, et al. Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc Natl Acad Sci USA. 1997;94(18):9848–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Sewell AK, Price DA, Oxenius A, Kelleher AD, Phillips RE. Cytotoxic T lymphocyte responses to human immunodeficiency virus: control and escape. Stem Cells. 2000;18(4):230–44.PubMedCrossRefGoogle Scholar
  70. 70.
    Shankar P, Russo M, Harnisch B, Patterson M, Skolnik P, Lieberman J. Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection. Blood. 2000;96(9):3094–101.PubMedGoogle Scholar
  71. 71.
    Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med. 2002;8(4):379–85.PubMedCrossRefGoogle Scholar
  72. 72.
    Kostense S, Vandenberghe K, Joling J, Van Baarle D, Nanlohy N, Manting E, et al. Persistent numbers of tetramer+CD8(+) T cells, but loss of interferon-gamma+HIV-specific T cells during progression to AIDS. Blood. 2002;99(7):2505–11.PubMedCrossRefGoogle Scholar
  73. 73.
    Oxenius A, Sewell AK, Dawson SJ, Gunthard HF, Fischer M, Gillespie GM, et al. Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load. J Clin Immunol. 2002;22(6):363–74.PubMedCrossRefGoogle Scholar
  74. 74.
    Almanzar G, Schwaiger S, Jenewein B, Keller M, Herndler-Brandstetter D, Wurzner R, et al. 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. 2005;79(6):3675–83.PubMedCrossRefGoogle Scholar
  75. 75.
    Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA. 2009;106(21):8623–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, et al. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol. 2005;175(12):8218–25.PubMedGoogle Scholar
  77. 77.
    Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85.PubMedCrossRefGoogle Scholar
  78. 78.
    Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G. Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol. 2004;39(4):607–13.PubMedCrossRefGoogle Scholar
  79. 79.
    Bjorgo E, Tasken K. Novel mechanism of signaling by CD28. Immunol Lett. 2010;129(1):1–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007;178(12):7710–9.PubMedGoogle Scholar
  81. 81.
    Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology. 1996;88(4):501–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Vallejo AN, Nestel AR, Schirmer M, Weyand CM, Goronzy JJ. Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J Biol Chem. 1998;273(14):8119–29.PubMedCrossRefGoogle Scholar
  83. 83.
    Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996;97(9):2027–37.PubMedCrossRefGoogle Scholar
  84. 84.
    Kobayashi T, Okamoto S, Iwakami Y, Nakazawa A, Hisamatsu T, Chinen H, et al. Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes. Inflamm Bowel Dis. 2007;13(7):837–46.PubMedCrossRefGoogle Scholar
  85. 85.
    Wallace DL, Masters JE, de Lara CM, Henson SM, Worth A, Zhang Y, et al. Human cytomegalovirus-specific CD8(+) T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects. Immunology. 2010;132:27–38.PubMedCrossRefGoogle Scholar
  86. 86.
    Gupta S, Gollapudi S. Susceptibility of naïve and subsets of memory T cells to apoptosis via multiple signaling pathways. Autoimmun Rev. 2007;6(7):476–81.PubMedCrossRefGoogle Scholar
  87. 87.
    Borthwick NJ, Lowdell M, Salmon M, Akbar AN. Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000;12(7):1005–13.PubMedCrossRefGoogle Scholar
  88. 88.
    Geginat J, Lanzavecchia A, Sallusto F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood. 2003;101(11):4260–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.PubMedCrossRefGoogle Scholar
  90. 90.
    Fann M, Chiu WK, Wood 3rd WH. Levine BL, Becker KG and Weng NP: Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev. 2005;205:190–206.PubMedCrossRefGoogle Scholar
  91. 91.
    Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29(7):343–51.PubMedCrossRefGoogle Scholar
  92. 92.
    Lazuardi L, Herndler-Brandstetter D, Brunner S, Laschober GT, Lepperdinger G, Grubeck-Loebenstein B. Microarray analysis reveals similarity between CD8+CD28- T cells from young and elderly persons, but not of CD8+CD28+ T cells. Biogerontology. 2009;10(2):191–202.PubMedCrossRefGoogle Scholar
  93. 93.
    Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30(7):306–12.PubMedCrossRefGoogle Scholar
  94. 94.
    Hackl M, Brunner S, Fortschegger K, Schreiner C, Micutkova L, Muck C, et al. miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell. 2010;9(2):291–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Luo X, Tsai LM, Shen N, Yu D. Evidence for microRNA-mediated regulation in rheumatic diseases. Ann Rheum Dis. 2010;69 Suppl 1:i30–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Monteiro J, Batliwalla F, Ostrer H, Gregersen PK. Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol. 1996;156(10):3587–90.PubMedGoogle Scholar
  97. 97.
    Kovaiou RD, Weiskirchner I, Keller M, Pfister G, Cioca DP, Grubeck-Loebenstein B. Age-related differences in phenotype and function of CD4+ T cells are due to a phenotypic shift from naïve to memory effector CD4+ T cells. Int Immunol. 2005;17(10):1359–66.PubMedCrossRefGoogle Scholar
  98. 98.
    Kober J, Leitner J, Klauser C, Woitek R, Majdic O, Stockl J, et al. The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur J Immunol. 2008;38(10):2678–88.PubMedCrossRefGoogle Scholar
  99. 99.
    Chiu WK, Fann M, Weng NP. Generation and growth of CD28nullCD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol. 2006;177(11):7802–10.PubMedGoogle Scholar
  100. 100.
    Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci. 2000;908:244–54.PubMedCrossRefGoogle Scholar
  101. 101.
    Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB. Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009;30(7):351–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB. Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009;30(7):351–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, et al. 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. 2002;168(11):5893–9.PubMedGoogle Scholar
  104. 104.
    Blankenberg S, Rupprecht HJ, Bickel C, Espinola-Klein C, Rippin G, Hafner G, et al. Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. Circulation. 2001;103(24):2915–21.PubMedGoogle Scholar
  105. 105.
    Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, Emery V, et al. Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation. 2003;108(6):678–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Spyridopoulos I, Hoffmann J, Aicher A, Brummendorf TH, Doerr HW, Zeiher AM, et al. Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation. 2009;120(14):1364–72.PubMedCrossRefGoogle Scholar
  107. 107.
    Fish KN, Soderberg-Naucler C, Mills LK, Stenglein S, Nelson JA. Human cytomegalovirus persistently infects aortic endothelial cells. J Virol. 1998;72(7):5661–8.PubMedGoogle Scholar
  108. 108.
    Bentz GL, Yurochko AD. Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proc Natl Acad Sci USA. 2008;105(14):5531–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009;5(5):e1000427.PubMedCrossRefGoogle Scholar
  110. 110.
    Schirmer M, Goldberger C, Wurzner R, Duftner C, Pfeiffer KP, Clausen J, et al. Circulating cytotoxic CD8(+) CD28(-) T cells in ankylosing spondylitis. Arthritis Res. 2002;4(1):71–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Holland AM, van den Brink MR. Rejuvenation of the aging T cell compartment. Curr Opin Immunol. 2009;21(4):454–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen. J Exp Med. 2005;201(6):845–51.PubMedCrossRefGoogle Scholar
  113. 113.
    Hollander GA, Krenger W, Blazar BR. Emerging strategies to boost thymic function. Curr Opin Pharmacol. 2010;10(4):443–53.PubMedCrossRefGoogle Scholar
  114. 114.
    Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol. 2005;40(11):884–93.PubMedCrossRefGoogle Scholar
  115. 115.
    Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signal. 2009;21(6):827–35.PubMedCrossRefGoogle Scholar
  116. 116.
    Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem. 2010;285(19):14071–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12(9):814–22.PubMedCrossRefGoogle Scholar
  118. 118.
    Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining "clean" cells. Autophagy. 2005;1(3):131–40.PubMedCrossRefGoogle Scholar
  119. 119.
    Gerland LM, Genestier L, Peyrol S, Michallet MC, Hayette S, Urbanowicz I, et al. Autolysosomes accumulate during in vitro CD8+ T-lymphocyte aging and may participate in induced death sensitization of senescent cells. Exp Gerontol. 2004;39(5):789–800.PubMedCrossRefGoogle Scholar
  120. 120.
    Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305–14.PubMedCrossRefGoogle Scholar
  121. 121.
    Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol. 2009;44(11):727–32.PubMedCrossRefGoogle Scholar
  122. 122.
    Kaeberlein M. Burtner CR and Kennedy BK: Recent developments in yeast aging. PLoS Genet. 2007;3(5):e84.PubMedCrossRefGoogle Scholar
  123. 123.
    Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14(10):885–90.PubMedCrossRefGoogle Scholar
  124. 124.
    Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35–46.PubMedCrossRefGoogle Scholar
  125. 125.
    Vigne P, Tauc M, Frelin C. Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries. PLoS ONE. 2009;4(5):e5422.PubMedCrossRefGoogle Scholar
  126. 126.
    Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108–12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Christoph R. Arnold
    • 1
  • Juliane Wolf
    • 1
  • Stefan Brunner
    • 1
  • Dietmar Herndler-Brandstetter
    • 1
  • Beatrix Grubeck-Loebenstein
    • 1
    Email author
  1. 1.Immunology Division, Institute for Biomedical Aging ResearchAustrian Academy of SciencesInnsbruckAustria

Personalised recommendations