Understanding immunosenescence to improve responses to vaccines

Nature Immunology

Volumn 14, Issue 5, 2013, Pages 428-436

  Goronzy, Jörg J ^a,b   Weyand, Cornelia M ^a,b  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VA PALO ALTO HEALTH CARE SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD31 ANTIGEN; DIPHTHERIA PERTUSSIS TETANUS VACCINE; IMMUNOLOGICAL ADJUVANT; INFLUENZA VACCINE; METALLOTHIONEIN; MICRORNA; MICRORNA 181A; PERTUSSIS VACCINE; PNEUMOCOCCUS VACCINE; T LYMPHOCYTE RECEPTOR; TETANUS TOXOID; UNCLASSIFIED DRUG; VACCINE; VARICELLA ZOSTER VACCINE;

ADAPTIVE IMMUNITY; AGED; AGING; ANTIBODY RESPONSE; AUTOIMMUNITY; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL AGING; CHILDHOOD DISEASE; DIPHTHERIA; GENE REARRANGEMENT; GROUPS BY AGE; HERPES ZOSTER; HUMAN; HUMAN VERSUS ANIMAL COMPARISON; IMMUNOCOMPETENCE; IMMUNOLOGICAL MEMORY; IMMUNOSENESCENCE; INFLAMMATION; INFLUENZA; INNATE IMMUNITY; LYMPHOCYTE FUNCTION; NONHUMAN; PERTUSSIS; PNEUMOCOCCAL INFECTION; PRIORITY JOURNAL; RECEPTOR DOWN REGULATION; REVIEW; SPECIES DIFFERENCE; T LYMPHOCYTE; TETANUS; THYMUS FUNCTION; VACCINATION;

ADAPTIVE IMMUNITY; AGED; AGED, 80 AND OVER; AGING; ANIMALS; CELL AGING; COMMUNICABLE DISEASE CONTROL; HUMANS; IMMUNOCOMPETENCE; MICE; VACCINATION; VACCINES;

EID: 84876535364     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.2588     Document Type: Review

References (116)

1. Weng, N.P. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24, 495-499 (2006).
2. Goronzy, J.J. & Weyand, CM. Immune aging and autoimmunity. Cell Mol. Life Sci. 69, 1615-1623 (2012).
3. Goronzy, J.J. & Weyand, CM. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity-catalysts of autoimmunity and chronic infammation. Arthritis Res. Ther. 5, 225-234 (2003).
4. Shaw, A.C., Joshi, S., Greenwood, H., Panda, A. & Lord, J.M. Aging of the innate immune system. Curr. Opin. Immunol. 22, 507-513 (2010).
5. Kanapuru, B. & Ershler, W.B. Infammation, coagulation, and the pathway to frailty. Am. J. Med. 122, 605-613 (2009).
6. Cavanagh, M.M., Weyand, CM. & Goronzy, J.J. Chronic infammation and aging: DNA damage tips the balance. Curr. Opin. Immunol. 24, 488-493 (2012).
7. Boraschi, D. et al. Ageing and immunity: addressing immune senescence to ensure healthy ageing. Vaccine 28, 3627-3631 (2010).
8. Boraschi, D. et al. Ageing and Immunity. Sci. Transl. Med. (in the press).
9. McElhaney, J.E. & Effros, R.B. Immunosenescence: what does it mean to health outcomes in older adults? Curr. Opin. Immunol. 21, 418-424 (2009).
10. Thomas-Crusells, J., McElhaney, J.E. & Aguado, M.T. Report of the ad-hoc consultation on aging and immunization for a future WHO research agenda on life-course immunization. Vaccine 30, 6007-6012 (2012).
11. Chen, W.H. et al. Vaccination in the elderly: an immunological perspective. Trends Immunol. 30, 351-359 (2009).
12. R): results of two randomized trials. Vaccine 30, 1721-1728 (2012).
13. Jefferson, T. et al. Effcacy and effectiveness of infuenza vaccines in elderly people: a systematic review. Lancet 366, 1165-1174 (2005).
14. Nichol, K.L., Nordin, J.D., Nelson, D.B., Mullooly, J.P. & Hak, E. Effectiveness of infuenza vaccine in the community-dwelling elderly. N. Engl. J. Med. 357, 1373-1381 (2007).
15. Gagliardi, A.M., Gomes Silva, B.N., Torloni, M.R. & Soares, B.G. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst. Rev. 10, CD008858 (2012).
16. Levin, M.J. Immune senescence and vaccines to prevent herpes zoster in older persons. Curr. Opin. Immunol. 24, 494-500 (2012).
17. Denis, F. et al. Hepatitis-B vaccination in the elderly. J. Infect. Dis. 149, 1019 (1984).
18. Dormitzer, P.R. et al. Infuenza vaccine immunology. Immunol. Rev. 239, 167-177 (2011).
19. Jackson, M.L. et al. Infuenza vaccination and risk of community-acquired pneumonia in immunocompetent elderly people: a population-based, nested case-control study. Lancet 372, 398-405 (2008).
20. Wong, K., Campitelli, M.A., Stukel, T.A. & Kwong, J.C. Estimating infuenza vaccine effectiveness in community-dwelling elderly patients using the instrumental variable analysis method. Arch. Intern. Med. 172, 484-491 (2012).
21. Couch, R.B. et al. Safety and immunogenicity of a high dosage trivalent infuenza vaccine among elderly subjects. Vaccine 25, 7656-7663 (2007).
22. Khurana, S. et al. MF59 adjuvant enhances diversity and affnity of antibody-mediated immune response to pandemic infuenza vaccines. Sci. Transl. Med. 3, 85ra48 (2011).
23. Brown, L.E. The role of adjuvants in vaccines for seasonal and pandemic infuenza. Vaccine 28, 8043-8045 (2010).
24. Ambrose, CS., Luke, C. & Coelingh, K. Current status of live attenuated infuenza vaccine in the United States for seasonal and pandemic infuenza. Infuenza Other Respi. Viruses 2, 193-202 (2008).
25. Haynes, L. & Lefebvre, J.S. Age-related defciencies in antigen-specifc CD4 T cell responses: lessons from mouse models. Aging Dis. 2, 374-381 (2011).
26. Miller, C. & Kelsoe, G. Ig VH hypermutation is absent in the germinal centers of aged mice. J. Immunol. 155, 3377-3384 (1995).
27. Yang, X., Stedra, J. & Cerny, J. Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice. J. Exp. Med. 183, 959-970 (1996).
28. Linton, P.J. & Dorshkind, K. Age-related changes in lymphocyte development and function. Nat. Immunol. 5, 133-139 (2004).
29. den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288-297 (2012).
30. Blackman, M.A. & Woodland, D.L. The narrowing of the CD8 T cell repertoire in old age. Curr. Opin. Immunol. 23, 537-542 (2011).
31. Berent-Maoz, B., Montecino-Rodriguez, E. & Dorshkind, K. Genetic regulation of thymocyte progenitor aging. Semin. Immunol. 24, 303-308 (2012).
32. Chinn, I.K., Blackburn, CC, Manley, N.R. & Sempowski, G.D. Changes in primary lymphoid organs with aging. Semin. Immunol. 24, 309-320 (2012).
33. Dixit, V.D. Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence. Semin. Immunol. 24, 321-330 (2012).
34. Pang, W.W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl. Acad. Sci. USA 108, 20012-20017 (2011).
35. Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl. Acad. Sci. USA 107, 5465-5470 (2010).
36. Wang, J. et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 148, 1001-1014 (2012).
37. Guerrettaz, L.M., Johnson, S.A. & Cambier, J.C. Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging. Proc. Natl. Acad. Sci. USA 105, 11898-11902 (2008).
38. Kogut, I., Scholz, J.L., Cancro, M.P. & Cambier, J.C. B cell maintenance and function in aging. Semin. Immunol. 24, 342-349 (2012). Comprehensive review of the infuence of age on B cell generation, homeostasis and function.
39. Cancro, M.P. et al. B cells and aging: molecules and mechanisms. Trends Immunol. 30, 313-318 (2009).
40. Solana, R. et al. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin. Immunol. 24, 331-341 (2012).
41. Maue, A.C. et al. T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol. 30, 301-305 (2009).
42. Lang, A. & Nikolich-Zugich, J. Functional CD8 T cell memory responding to persistent latent infection is maintained for life. J. Immunol. 187, 3759-3768 (2011).
43. Sadighi Akha, A.A. & Miller, R.A. Signal transduction in the aging immune system. Curr. Opin. Immunol. 17, 486-491 (2005).
44. Haynes, L., Linton, P.J., Eaton, S.M., Tonkonogy, S.L. & Swain, S.L. Interleukin 2, but not other common γ chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J. Exp. Med. 190, 1013-1024 (1999).
45. Coffman, R.L., Sher, A. & Seder, R.A. Vaccine adjuvants: putting innate immunity to work. Immunity 33, 492-503 (2010).
46. Nikolich-Zugich, J., Li, G., Uhrlaub, J.L., Renkema, K.R. & Smithey, M.J. Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin. Immunol. 24, 356-364 (2012).
47. Decman, V. et al. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specifc precursors. J. Immunol. 188, 1933-1941 (2012).
48. + T cells. Immunol. Rev. 205, 220-228 (2005).
49. + T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl. Acad. Sci. USA 108, 13694-13699 (2011).
50. INK4a prevents cancer and promotes aging in lymphocytes. Blood 117, 3257-3267 (2011).
51. High, K.P., Akbar, A.N. & Nikolich-Zugich, J. Translational research in immune senescence: assessing the relevance of current models. Semin. Immunol. 24, 373-382 (2012).
52. Davis, M.M. Immunology taught by humans. Sci. Transl. Med. 4, 117fs112 (2012).
53. Mestas, J. & Hughes, C.C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731-2738 (2004).
54. Nikolich-Zugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8, 512-522 (2008).
55. + memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373-383 (2013).
56. Jiang, N. et al. Lineage structure of the human antibody repertoire in response to infuenza vaccination. Sci Transl Med 5, 171ra119 (2013).
57. Li, G.M. et al. Pandemic H1N1 infuenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc. Natl. Acad. Sci. USA 109, 9047-9052 (2012).
58. Virgin, H.W., Wherry, E.J. & Ahmed, R. Redefning chronic viral infection. Cell 138, 30-50 (2009).
59. Pawelec, G., McElhaney, J.E., Aiello, A.E. & Derhovanessian, E. The impact of CMV infection on survival in older humans. Curr. Opin. Immunol. 24, 507-511 (2012).
60. Goronzy, J.J. et al. Value of immunological markers in predicting responsiveness to infuenza vaccination in elderly individuals. J. Virol. 75, 12182-12187 (2001).
61. - T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J. Immunol. 168, 5893-5899 (2002).
62. Andrews, N.P., Fujii, H., Goronzy, J.J. & Weyand, C.M. Telomeres and immunological diseases of aging. Gerontology 56, 390-403 (2010).
63. Goronzy, J.J., Shao, L. & Weyand, C.M. Immune aging and rheumatoid arthritis. Rheum. Dis. Clin. North Am. 36, 297-310 (2010).
64. Smithey, M.J., Li, G., Venturi, V., Davenport, M.P. & Nikolich-Zugich, J. Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. J. Immunol. 189, 5356-5366 (2012).
65. Cicin-Sain, L. et al. Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog. 8, e1002849 (2012).
66. Mekker, A. et al. Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 8, e1002850 (2012).
67. Mandal, P.K. & Rossi, D.J. DNA-damage-induced differentiation in hematopoietic stem cells. Cell 148, 847-848 (2012).
68. Colmegna, I. et al. Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum. 58, 990-1000 (2008).
69. Ademokun, A., Wu, Y.C. & Dunn-Walters, D. The ageing B cell population: composition and function. Biogerontology 11, 125-137 (2010).
70. Dunn-Walters, D.K. & Ademokun, A.A. B cell repertoire and ageing. Curr. Opin. Immunol. 22, 514-520 (2010).
71. Gibson, K.L. et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8, 18-25 (2009).
72. Steinmann, G.G., Klaus, B. & Muller-Hermelink, H.K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand. J. Immunol. 22, 563-575 (1985).
73. Hakim, F.T. et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J. Clin. Invest. 115, 930-939 (2005).
74. Castermans, E. et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica 96, 298-306 (2011).
75. Dowling, M.R. & Hodgkin, P.D. Why does the thymus involute? A selection-based hypothesis. Trends Immunol. 30, 295-300 (2009).
76. Aspinall, R., Pitts, D., Lapenna, A. & Mitchell, W. Immunity in the elderly: the role of the thymus. J. Comp. Pathol. 142 (suppl. 1), S111-S115 (2010).
77. Douek, D.C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690-695 (1998).
78. Naylor, K. et al. The infuence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446-7452 (2005).
79. Dutilh, B.E. & de Boer, R.J. Decline in excision circles requires homeostatic renewal or homeostatic death of naive T cells. J. Theor. Biol. 224, 351-358 (2003).
80. Hazenberg, M.D., Borghans, J.A., de Boer, R.J. & Miedema, F. Thymic output: a bad TREC record. Nat. Immunol. 4, 97-99 (2003).
81. Sauce, D. et al. Evidence of premature immune aging in patients thymectomized during early childhood. J. Clin. Invest. 119, 3070-3078 (2009).
82. Sauce, D. & Appay, V. Altered thymic activity in early life: how does it affect the immune system in young adults? Curr. Opin. Immunol. 23, 543-548 (2011).
83. Czesnikiewicz-Guzik, M. et al. T cell subset-specifc susceptibility to aging. Clin. Immunol. 127, 107-118 (2008).
84. Kimmig, S. et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789-794 (2002).
85. + T cells constrains the TCR repertoire in healthy human adults. Eur. J. Immunol. 35, 1987-1994 (2005).
86. Goronzy, J.J. & Weyand, C.M. T cell development and receptor diversity during aging. Curr. Opin. Immunol. 17, 468-475 (2005).
87. Cicin-Sain, L. et al. Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc. Natl. Acad. Sci. USA 104, 19960-19965 (2007).
88. Johnson, P.L., Yates, A.J., Goronzy, J.J. & Antia, R. Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age. Proc. Natl. Acad. Sci. USA 109, 21432-21437 (2012).
89. Wils, E.J. et al. Insuffcient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Haematologica 96, 1846-1854 (2011).
90. Gomez, I., Marx, F., Gould, E.A. & Grubeck-Loebenstein, B. T cells from elderly persons respond to neoantigenic stimulation with an unimpaired IL-2 production and an enhanced differentiation into effector cells. Exp. Gerontol. 39, 597-605 (2004).
91. Lee, W.W. et al. Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling. Rejuvenation Res. 11, 1001-1011 (2008).
92. Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518-1524 (2012). Study identifying a negative feedback loop in TCR signaling that accounts for diminished T cell responsiveness in the elderly and is controlled by miR-181a.
93. Li, Q.J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147-161 (2007).
94. Goronzy, J.J., Li, G., Yu, M. & Weyand, CM. Signaling pathways in aged T cells- a refection of T cell differentiation, cell senescence and host environment. Semin. Immunol. 24, 365-372 (2012).
95. Adachi, K. & Davis, M.M. T-cell receptor ligation induces distinct signaling pathways in naive vs. antigen-experienced T cells. Proc. Natl. Acad. Sci. USA 108, 1549-1554 (2011).
96. Fragoso, R. et al. Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1. PLoS Genet. 8, e1002855 (2012).
97. Wang, G.C., Dash, P., McCullers, J.A., Doherty, P.C. & Thomas, P.G. T cell receptor aß diversity inversely correlates with pathogen-specifc antibody levels in human cytomegalovirus infection. Sci. Transl. Med. 4, 128ra142 (2012).
98. Maciver, N.J., Michalek, R.D. & Rathmell, J.C. Metabolic Regulation of T Lymphocytes. Annu. Rev. Immunol. 31, 259-283 (2013).
99. Yu, M. et al. Signal inhibition by the dual-specifc phosphatase 4 impairs T cell-dependent B-cell responses with age. Proc. Natl. Acad. Sci. USA 109, E879-E888 (2012).
100. Shao, L. et al. Defciency of the DNA repair enzyme ATM in rheumatoid arthritis. J. Exp. Med. 206, 1435-1449 (2009).
101. Liu, Y. & Sharpless, N.E. Tumor suppressor mechanisms in immune aging. Curr. Opin. Immunol. 21, 431-439 (2009).
102. Di Mitri, D. et al. Reversible senescence in human CD4+CD45RA+CD27-memory T cells. J. Immunol. 187, 2093-2100 (2011).
103. Effros, R.B. Telomerase induction in T cells: a cure for aging and disease? Exp. Gerontol. 42, 416-420 (2007).
104. Fujii, H., Shao, L., Colmegna, I., Goronzy, J.J. & Weyand, CM. Telomerase insuffciency in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 106, 4360-4365 (2009).
105. Shao, L., Goronzy, J.J. & Weyand, CM. DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis. EMBO Mol. Med. 2, 415-427 (2010).
106. Weng, N.P., Akbar, A.N. & Goronzy, J. CD28-T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306-312 (2009).
107. Cavanagh, M.M., Qi, Q., Weyand, CM. & Goronzy, J.J. Finding balance: T cell regulatory receptor expression during aging. Aging Dis. 2, 398-413 (2011).
108. Francisco, L.M., Sage, P.T. & Sharpe, A.H. The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219-242 (2010).
109. Wherry, E.J. T cell exhaustion. Nat. Immunol. 12, 492-499 (2011).
110. Akbar, A.N. & Henson, S.M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289-295 (2011).
111. Frasca, D. & Blomberg, B.B. Aging impairs murine B cell differentiation and function in primary and secondary lymphoid tissues. Aging Dis. 2, 361-373 (2011).
112. Wrammert, J. et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 infuenza virus infection. J. Exp. Med. 208, 181-193 (2011).
113. Sasaki, S. et al. Limited effcacy of inactivated infuenza vaccine in elderly individuals is associated with decreased production of vaccine-specifc antibodies. J. Clin. Invest. 121, 3109-3119 (2011).
114. Khurana, S., Frasca, D., Blomberg, B. & Golding, H. AID activity in B cells strongly correlates with polyclonal antibody affnity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog. 8, e1002920 (2012).
115. Frasca, D. et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J. Immunol. 180, 5283-5290 (2008).
116. Vukmanovic-Stejic, M., Rustin, M.H., Nikolich-Zugich, J. & Akbar, A.N. Immune responses in the skin in old age. Curr. Opin. Immunol. 23, 525-531 (2011).