Cellular and Molecular Life Sciences

, Volume 69, Issue 10, pp 1615–1623 | Cite as

Immune aging and autoimmunity

  • Jörg J. GoronzyEmail author
  • Cornelia M. Weyand
Multi-author review


Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses.


Age Autoimmunity T cell memory T cell homeostasis CD45RA T effector cells 



Ataxia telangiectasia mutated




Highly active antiretroviral therapy


Immune reconstitution inflammatory syndrome


Killer immunoglobulin-like receptors


T cell receptor excision circle



This work was supported by grants from the National Institutes of Health (AI 57266 and AI 90019).


  1. 1.
    Christen U, Hintermann E, Holdener M, von Herrath MG (2010) Viral triggers for autoimmunity: is the ‘glass of molecular mimicry’ half full or half empty? J Autoimmun 34:38–44PubMedCrossRefGoogle Scholar
  2. 2.
    Green NM, Marshak-Rothstein A (2011) Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol 23(2):106–112PubMedCrossRefGoogle Scholar
  3. 3.
    Shlomchik MJ (2009) Activating systemic autoimmunity: B’s, T’s, and tolls. Curr Opin Immunol 21:626–633PubMedCrossRefGoogle Scholar
  4. 4.
    Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N et al (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179–186PubMedCrossRefGoogle Scholar
  5. 5.
    Rivetti D, Jefferson T, Thomas R, Rudin M, Rivetti A, et al (2006) Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 3:CD004876Google Scholar
  6. 6.
    Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24:1159–1169PubMedCrossRefGoogle Scholar
  7. 7.
    Arvin AM (2008) Humoral and cellular immunity to varicella-zoster virus: an overview. J Infect Dis 197(Suppl 2):S58–S60PubMedCrossRefGoogle Scholar
  8. 8.
    Goronzy JJ, Weyand CM (2003) Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity—catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther 5:225–234PubMedCrossRefGoogle Scholar
  9. 9.
    Ruffatti A, Rossi L, Calligaro A, Del Ross T, Lagni M et al (1990) Autoantibodies of systemic rheumatic diseases in the healthy elderly. Gerontology 36:104–111PubMedCrossRefGoogle Scholar
  10. 10.
    Moulias R, Proust J, Wang A, Congy F, Marescot MR et al (1984) Age-related increase in autoantibodies. Lancet 1:1128–1129PubMedCrossRefGoogle Scholar
  11. 11.
    Weyand CM, Goronzy JJ (2003) Medium- and large-vessel vasculitis. N Engl J Med 349:160–169PubMedCrossRefGoogle Scholar
  12. 12.
    Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE (2002) Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 46:625–631PubMedCrossRefGoogle Scholar
  13. 13.
    Goronzy JJ, Weyand CM (2005) Rheumatoid arthritis. Immunol Rev 204:55–73PubMedCrossRefGoogle Scholar
  14. 14.
    Goronzy JJ, Shao L, Weyand CM (2010) Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am 36:297–310PubMedCrossRefGoogle Scholar
  15. 15.
    Weng NP (2006) Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24:495–499PubMedCrossRefGoogle Scholar
  16. 16.
    Kong FK, Chen CL, Six A, Hockett RD, Cooper MD (1999) T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc Natl Acad Sci USA 96:1536–1540PubMedCrossRefGoogle Scholar
  17. 17.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM et al (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695PubMedCrossRefGoogle Scholar
  18. 18.
    Hazenberg MD, Borghans JA, de Boer RJ, Miedema F (2003) Thymic output: a bad TREC record. Nat Immunol 4:97–99PubMedCrossRefGoogle Scholar
  19. 19.
    Naylor K, Li G, Vallejo AN, Lee WW, Koetz K et al (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174:7446–7452PubMedGoogle Scholar
  20. 20.
    Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opin Immunol 17:468–475PubMedCrossRefGoogle Scholar
  21. 21.
    Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK et al (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115:930–939PubMedGoogle Scholar
  22. 22.
    Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ et al (2000) T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 97:9203–9208PubMedCrossRefGoogle Scholar
  23. 23.
    Surh CD, Sprent J (2008) Homeostasis of naive and memory T cells. Immunity 29:848–862PubMedCrossRefGoogle Scholar
  24. 24.
    Wallace DL, Zhang Y, Ghattas H, Worth A, Irvine A et al (2004) Direct measurement of T cell subset kinetics in vivo in elderly men and women. J Immunol 173:1787–1794PubMedGoogle Scholar
  25. 25.
    Cicin-Sain L, Messaoudi I, Park B, Currier N, Planer S 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 104:19960–19965PubMedCrossRefGoogle Scholar
  26. 26.
    Labrecque N, Whitfield LS, Obst R, Waltzinger C, Benoist C et al (2001) How much TCR does a T cell need? Immunity 15:71–82PubMedCrossRefGoogle Scholar
  27. 27.
    Polic B, Kunkel D, Scheffold A, Rajewsky K (2001) How alpha beta T cells deal with induced TCR alpha ablation. Proc Natl Acad Sci USA 98:8744–8749PubMedCrossRefGoogle Scholar
  28. 28.
    Seddon B, Zamoyska R (2002) TCR and IL-7 receptor signals can operate independently or synergize to promote lymphopenia-induced expansion of naive T cells. J Immunol 169:3752–3759PubMedGoogle Scholar
  29. 29.
    Kassiotis G, Zamoyska R, Stockinger B (2003) Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J Exp Med 197:1007–1016PubMedCrossRefGoogle Scholar
  30. 30.
    Kieper WC, Burghardt JT, Surh CD (2004) A role for TCR affinity in regulating naive T cell homeostasis. J Immunol 172:40–44PubMedGoogle Scholar
  31. 31.
    Goronzy JJ, Weyand CM (2001) T cell homeostasis and autoreactivity in rheumatoid arthritis. Curr Dir Autoimmun 3:112–132PubMedCrossRefGoogle Scholar
  32. 32.
    Goronzy JJ, Weyand CM (2001) Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol 22:251–255PubMedCrossRefGoogle Scholar
  33. 33.
    Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J et al (2000) Diversity of human alpha beta T cell receptors. Science 288:1135PubMedCrossRefGoogle Scholar
  34. 34.
    Wagner UG, Koetz K, Weyand CM, Goronzy JJ (1998) Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA 95:14447–14452PubMedCrossRefGoogle Scholar
  35. 35.
    Warren RL, Freeman JD, Zeng T, Choe G, Munro S et al (2011) Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res 21(5):790–797PubMedCrossRefGoogle Scholar
  36. 36.
    Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, et al (2010) Overlap and effective size of the human CD8+ T cell receptor repertoire. Sci Transl Med 2:47ra64Google Scholar
  37. 37.
    Cho BK, Rao VP, Ge Q, Eisen HN, Chen J (2000) Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 192:549–556PubMedCrossRefGoogle Scholar
  38. 38.
    Goldrath AW, Bogatzki LY, Bevan MJ (2000) Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med 192:557–564PubMedCrossRefGoogle Scholar
  39. 39.
    Goldrath AW, Luckey CJ, Park R, Benoist C, Mathis D (2004) The molecular program induced in T cells undergoing homeostatic proliferation. Proc Natl Acad Sci USA 101:16885–16890PubMedCrossRefGoogle Scholar
  40. 40.
    Williams KM, Hakim FT, Gress RE (2007) T cell immune reconstitution following lymphodepletion. Semin Immunol 19:318–330PubMedCrossRefGoogle Scholar
  41. 41.
    Jendro MC, Ganten T, Matteson EL, Weyand CM, Goronzy JJ (1995) Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum 38:1242–1251PubMedCrossRefGoogle Scholar
  42. 42.
    Akbar AN, Fletcher JM (2005) Memory T cell homeostasis and senescence during aging. Curr Opin Immunol 17:480–485PubMedCrossRefGoogle Scholar
  43. 43.
    Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8:512–522PubMedCrossRefGoogle Scholar
  44. 44.
    Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL et al (2008) T cell subset-specific susceptibility to aging. Clin Immunol 127:107–118PubMedCrossRefGoogle Scholar
  45. 45.
    Effros RB, Dagarag M, Spaulding C, Man J (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157PubMedCrossRefGoogle Scholar
  46. 46.
    Weng NP, Akbar AN, Goronzy J (2009) CD28(−) T cells: their role in the age-associated decline of immune function. Trends Immunol 30:306–312PubMedCrossRefGoogle Scholar
  47. 47.
    Moss P (2010) The emerging role of cytomegalovirus in driving immune senescence: a novel therapeutic opportunity for improving health in the elderly. Curr Opin Immunol 22:529–534PubMedCrossRefGoogle Scholar
  48. 48.
    Schmidt D, Goronzy JJ, Weyand CM (1996) CD4+ CD7− CD28− T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 97:2027–2037PubMedCrossRefGoogle Scholar
  49. 49.
    Zal B, Kaski JC, Arno G, Akiyu JP, Xu Q et al (2004) Heat-shock protein 60-reactive CD4+ CD28 null T cells in patients with acute coronary syndromes. Circulation 109:1230–1235PubMedCrossRefGoogle Scholar
  50. 50.
    Messaoudi I, Warner J, Nikolich-Zugich D, Fischer M, Nikolich-Zugich J (2006) Molecular, cellular, and antigen requirements for development of age-associated T cell clonal expansions in vivo. J Immunol 176:301–308PubMedGoogle Scholar
  51. 51.
    Zhang R, Shah MV, Loughran TP Jr (2010) The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders. Hematol Oncol 28:105–117PubMedGoogle Scholar
  52. 52.
    Shah MV, Zhang R, Loughran TP Jr (2009) Never say die: survival signaling in large granular lymphocyte leukemia. Clin Lymphoma Myeloma 9(Suppl 3):S244–S253PubMedGoogle Scholar
  53. 53.
    Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ (1998) Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+ CD28− T cells from rheumatoid arthritis patients. J Immunol 161:1018–1025PubMedGoogle Scholar
  54. 54.
    Park W, Weyand CM, Schmidt D, Goronzy JJ (1997) Co-stimulatory pathways controlling activation and peripheral tolerance of human CD4 + CD28− T cells. Eur J Immunol 27:1082–1090PubMedCrossRefGoogle Scholar
  55. 55.
    Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ (1998) Functional properties of CD4 + CD28− T cells in the aging immune system. Mech Ageing Dev 102:131–147PubMedCrossRefGoogle Scholar
  56. 56.
    Serriari NE, Gondois-Rey F, Guillaume Y, Remmerswaal EB, Pastor S et al (2010) B and T lymphocyte attenuator is highly expressed on CMV-specific T cells during infection and regulates their function. J Immunol 185:3140–3148PubMedCrossRefGoogle Scholar
  57. 57.
    Fann M, Chiu WK, Wood WH 3rd, Levine BL, Becker KG et al (2005) Gene expression characteristics of CD28 null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev 205:190–206PubMedCrossRefGoogle Scholar
  58. 58.
    Warrington KJ, Takemura S, Goronzy JJ, Weyand CM (2001) CD4+, CD28− T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum 44:13–20PubMedCrossRefGoogle Scholar
  59. 59.
    Namekawa T, Snyder MR, Yen JH, Goehring BE, Leibson PJ et al (2000) Killer cell activating receptors function as costimulatory molecules on CD4+ CD28 null T cells clonally expanded in rheumatoid arthritis. J Immunol 165:1138–1145PubMedGoogle Scholar
  60. 60.
    Bigouret V, Hoffmann T, Arlettaz L, Villard J, Colonna M et al (2003) Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood 101:3198–3204PubMedCrossRefGoogle Scholar
  61. 61.
    Snyder MR, Muegge LO, Offord C, O’Fallon WM, Bajzer Z et al (2002) Formation of the killer Ig-like receptor repertoire on CD4+ CD28 null T cells. J Immunol 168:3839–3846PubMedGoogle Scholar
  62. 62.
    Chen X, Bai F, Sokol L, Zhou J, Ren A et al (2009) A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia. Blood 113:3226–3234PubMedCrossRefGoogle Scholar
  63. 63.
    Hickman SP, Turka LA (2005) Homeostatic T cell proliferation as a barrier to T cell tolerance. Philos Trans R Soc Lond B Biol Sci 360:1713–1721PubMedCrossRefGoogle Scholar
  64. 64.
    Ramanathan S, Poussier P (2001) BB rat lyp mutation and Type 1 diabetes. Immunol Rev 184:161–171PubMedCrossRefGoogle Scholar
  65. 65.
    King C, Ilic A, Koelsch K, Sarvetnick N (2004) Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117:265–277PubMedCrossRefGoogle Scholar
  66. 66.
    Calzascia T, Pellegrini M, Lin A, Garza KM, Elford AR et al (2008) CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci USA 105:2999–3004PubMedCrossRefGoogle Scholar
  67. 67.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T et al (2007) T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17 + Th cells that cause autoimmune arthritis. J Exp Med 204:41–47PubMedCrossRefGoogle Scholar
  68. 68.
    Muller M, Wandel S, Colebunders R, Attia S, Furrer H et al (2010) Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 10:251–261PubMedCrossRefGoogle Scholar
  69. 69.
    Thewissen M, Somers V, Venken K, Linsen L, van Paassen P et al (2007) Analyses of immunosenescent markers in patients with autoimmune disease. Clin Immunol 123:209–218PubMedCrossRefGoogle Scholar
  70. 70.
    Goronzy JJ, Matteson EL, Fulbright JW, Warrington KJ, Chang-Miller A et al (2004) Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum 50:43–54PubMedCrossRefGoogle Scholar
  71. 71.
    Schönland SO, Lopez C, Widmann T, Zimmer J, Bryl E, Goronzy JJ, Weyand CM (2003) Premature telomeric loss in rheumatoid arthritis is genetically determined and involves lymphoid and myeloid cell lineages. Proc Natl Acad Sci USA 100:13471–13476PubMedCrossRefGoogle Scholar
  72. 72.
    Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ et al (2008) Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum 58:990–1000PubMedCrossRefGoogle Scholar
  73. 73.
    Beerman I, Maloney WJ, Weissmann IL, Rossi DJ (2010) Stem cells and the aging hematopoietic system. Curr Opin Immunol 22:500–506PubMedCrossRefGoogle Scholar
  74. 74.
    Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM (2009) Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA 106:4360–4365PubMedCrossRefGoogle Scholar
  75. 75.
    Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ et al (2009) Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J Exp Med 206:1435–1449PubMedCrossRefGoogle Scholar
  76. 76.
    Martens PB, Goronzy JJ, Schaid D, Weyand CM (1997) Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum 40:1106–1114PubMedCrossRefGoogle Scholar
  77. 77.
    Komocsi A, Lamprecht P, Csernok E, Mueller A, Holl-Ulrich K et al (2002) Peripheral blood and granuloma CD4(+)CD28(−) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener’s granulomatosis. Am J Pathol 160:1717–1724PubMedCrossRefGoogle Scholar
  78. 78.
    McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, et al. (2010) A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 16:581, 586–591Google Scholar
  79. 79.
    Wilde B, Thewissen M, Damoiseaux J, van Paassen P, Witzke O et al (2010) T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells? Arthritis Res Ther 12:204PubMedCrossRefGoogle Scholar
  80. 80.
    Berden AE, Kallenberg CG, Savage CO, Yard BA, Abdulahad WH et al (2009) Cellular immunity in Wegener’s granulomatosis: characterizing T lymphocytes. Arthritis Rheum 60:1578–1587PubMedCrossRefGoogle Scholar
  81. 81.
    Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR et al (2000) Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101:2883–2888PubMedGoogle Scholar
  82. 82.
    Nakajima T, Schulte S, Warrington KJ, Kopecky SL, Frye RL et al (2002) T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation 105:570–575PubMedCrossRefGoogle Scholar
  83. 83.
    Sato K, Niessner A, Kopecky SL, Frye RL, Goronzy JJ et al (2006) TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque. J Exp Med 203:239–250PubMedCrossRefGoogle Scholar
  84. 84.
    Pryshchep S, Sato K, Goronzy JJ, Weyand CM (2006) T cell recognition and killing of vascular smooth muscle cells in acute coronary syndrome. Circ Res 98:1168–1176PubMedCrossRefGoogle Scholar
  85. 85.
    Snyder MR, Weyand CM, Goronzy JJ (2004) The double life of NK receptors: stimulation or co-stimulation? Trends Immunol 25:25–32PubMedCrossRefGoogle Scholar
  86. 86.
    Eagle RA, Trowsdale J (2007) Promiscuity and the single receptor: NKG2D. Nat Rev Immunol 7:737–744PubMedCrossRefGoogle Scholar
  87. 87.
    Van Belle TL, von Herrath MG (2009) The role of the activating receptor NKG2D in autoimmunity. Mol Immunol 47:8–11PubMedCrossRefGoogle Scholar
  88. 88.
    Snyder MR, Lucas M, Vivier E, Weyand CM, Goronzy JJ (2003) Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4+ T cells. J Exp Med 197:437–449PubMedCrossRefGoogle Scholar
  89. 89.
    Sawai H, Park YW, Roberson J, Imai T, Goronzy JJ et al (2005) T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum 52:1392–1401PubMedCrossRefGoogle Scholar
  90. 90.
    Goodnow CC (2007) Multistep pathogenesis of autoimmune disease. Cell 130:25–35PubMedCrossRefGoogle Scholar

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© Springer Basel AG (outside the USA) 2012

Authors and Affiliations

  1. 1.Division of Immunology and Rheumatology, Department of MedicineStanford University School of MedicineStanfordUSA

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