Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?

Nature Reviews Immunology

Volumn 11, Issue 4, 2011, Pages 289-295

  Akbar, Arne N ^a   Henson, Sian M ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

B LYMPHOCYTE INDUCED MATURATION PROTEIN 1; BIM PROTEIN; CD27 ANTIGEN; CD28 ANTIGEN; CD40 LIGAND; CD45RA ANTIGEN; CD57 ANTIGEN; CHECKPOINT KINASE 2; CHEMOKINE RECEPTOR CCR7; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DNA; GAMMA INTERFERON; GRANZYME B; INTERLEUKIN 2; KILLER CELL LECTIN LIKE RECEPTOR SUBFAMILY G; LYMPHOCYTE ACTIVATION GENE 3 PROTEIN; LYMPHOCYTE ANTIGEN; MUCIN; NATURAL KILLER CELL LECTIN LIKE RECEPTOR; PERFORIN; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN BCL 2; PROTEIN KINASE B; PROTEIN P21; PROTEIN P53; SYNAPTOPHYSIN; T CELL IMMUNOGLOBULIN DOMAIN AND MUCIN DOMAIN PROTEIN 3; T LYMPHOCYTE RECEPTOR; TELOMERASE; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG;

ANTIGEN EXPRESSION; APOPTOSIS; CD8+ T LYMPHOCYTE; CELL AGING; CELL CYCLE ARREST; CELL DEATH; CELL DIVISION; CELL FUNCTION; CELL GROWTH; CELL SURFACE; CELL SURVIVAL; CYTOKINE PRODUCTION; CYTOTOXICITY; DNA DAMAGE; EPSTEIN BARR VIRUS; EPSTEIN BARR VIRUS INFECTION; EXHAUSTION; FIBROBLAST; HUMAN; IMMUNE RESPONSE; IMMUNITY; IN VITRO STUDY; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE PROLIFERATION; MEDIATOR; MEMORY T LYMPHOCYTE; MOLECULAR BIOLOGY; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TELOMERE; VIRUS INFECTION;

ANIMALS; CELL AGING; FATIGUE; HUMANS; IMMUNITY, CELLULAR; LYMPHOCYTE ACTIVATION; MICE; T-LYMPHOCYTES; VIRUS DISEASES;

EID: 79953159005     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2959     Document Type: Review

References (95)

1. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687 (2006). (Pubitemid 43237609)
2. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nature Immunol. 10, 29-37 (2009).
3. Freeman, G. J., Wherry, E. J., Ahmed, R. & Sharpe, A. H. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223-2227 (2006). (Pubitemid 44498355)
4. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350-354 (2006). (Pubitemid 44435155)
5. Akbar, A. N. & Vukmanovic-Stejic, M. Telomerase in T lymphocytes: use it and lose iT J. Immunol. 178, 6689-6694 (2007).
6. Hodes, R. J., Hathcock, K. S. & Weng, N. P. Telomeres in T and B cells. Nature Rev. Immunol. 2, 699-706 (2002). (Pubitemid 37328727)
7. Effros, R. B., Dagarag, M., Spaulding, C. & Man, J. The role of CD8+ T-cell replicative senescence in human aging. Immunol. Rev. 205, 147-157 (2005). (Pubitemid 40780183)
8. Voehringer, D. et al. Viral infections induce abundant numbers of senescent CD8 T cells. J. Immunol. 167, 4838-4843 (2001). (Pubitemid 33009711)
9. Fletcher, J. M. et al. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J. Immunol. 175, 8218-8225 (2005). (Pubitemid 41798386)
10. Appay, V., Almeida, J. R., Sauce, D., Autran, B. & Papagno, L. Accelerated immune senescence and HIV-1 infection. Exp. Gerontol. 42, 432-437 (2007). (Pubitemid 46561182)
11. d'Adda di Fagagna F., et al., A DNA damage checkpoint response in telomere-initiated senescence, Nature, 426, 194-198 (2003). (Pubitemid 37442589)
12. Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010).
13. Akbar, A. N., Beverley, P. C. & Salmon, M. Will telomere erosion lead to a loss of T-cell memory? Nature Rev. Immunol. 4, 737-743 (2004). (Pubitemid 39223079)
14. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614-636 (1965).
15. Blackburn, E. H. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 579, 859-862 (2005). (Pubitemid 40361854)
16. Campisi, J. & d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729-740 (2007). (Pubitemid 47312822)
17. d'Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer, 8, 512-522 (2008). (Pubitemid 351881854)
18. Passos, J. F. & Von Zglinicki, T. Oxygen free radicals in cell senescence: are they signal transducers? Free Radic. Res. 40, 1277-1283 (2006). (Pubitemid 44698277)
19. Rufer, N. et al. Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions. Blood 102, 1779-1787 (2003). (Pubitemid 37022574)
20. Plunkett, F. J. et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J. Immunol. 178, 7710-7719 (2007). (Pubitemid 46898042)
21. Plunkett, F. J. et al. The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech. Ageing Dev. 126, 855-865 (2005). (Pubitemid 40909782)
22. Migliaccio, M., Raj, K., Menzel, O. & Rufer, N. Mechanisms that limit the in vitro proliferative potential of human CD8+ T lymphocytes. J. Immunol. 174, 3335-3343 (2005). (Pubitemid 40354037)
23. Akbar, A. N., Soares, M. V., Plunkett, F. J. & Salmon, M. Differential regulation of CD8+ T cell senescence in mice and men. Mech. Ageing Dev. 121, 69-76 (2000). (Pubitemid 32115401)
24. Itahana, K., Campisi, J. & Dimri, G. P. Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5, 1-10 (2004). (Pubitemid 38461023)
25. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501-513 (2004). (Pubitemid 38648803)
26. Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131-144 (2003). (Pubitemid 36511698)
27. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155-168 (2003). (Pubitemid 37328868)
28. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513-522 (2005). (Pubitemid 40269765)
29. Reed, J. R. et al. Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J. Exp. Med. 199, 1433-1443 (2004). (Pubitemid 38685734)
30. Effros, R. B. Replicative senescence of CD8 T cells: effect on human ageing. Exp. Gerontol. 39, 517-524 (2004). (Pubitemid 38402077)
31. Nikolich-žugich, J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nature Rev. Immunol. 8, 512-522 (2008). (Pubitemid 351913675)
32. Akbar, A. N. & Fletcher, J. M. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17, 480-485 (2005). (Pubitemid 41207950)
33. Goronzy, J. J., Lee, W. W. & Weyand, C. M. Aging and T-cell diversity. Exp. Gerontol. 42, 400-406 (2007). (Pubitemid 46561179)
34. Spaulding, C., Guo, W. & Effros, R. B. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp. Gerontol. 34, 633-644 (1999). (Pubitemid 29420328)
35. Pawelec, G., Wagner, W., Adibzadeh, M. & Engel, A. T cell immunosenescence in vitro and in vivo. Exp. Gerontol. 34, 419-429 (1999). (Pubitemid 29293619)
36. Libri, V. et al. Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27- T cells: the potential involvement of interleukin-7 in this process. Immunology 132, 326-339 (2011).
37. Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nature Med. 8, 379-385 (2002). (Pubitemid 34407033)
38. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745-763 (2004). (Pubitemid 38680440)
39. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407-1418 (1997). (Pubitemid 27479800)
40. Roth, A. et al. Telomerase levels control the lifespan of human T lymphocytes. Blood 102, 849-857 (2003). (Pubitemid 36917775)
41. Faragher, R. G. & Kipling, D. How might replicative senescence contribute to human ageinG Bioessays 20, 985-991 (1998). (Pubitemid 29032176)
42. Akbar, A. N. & Salmon, M. Cellular environments and apoptosis: tissue microenvironments control activated T-cell death. Immunol. Today 18, 72-76 (1997). (Pubitemid 27107100)
43. Pawelec, G. et al. Human immunosenescence: is it infectious? Immunol. Rev. 205, 257-268 (2005). (Pubitemid 40780191)
44. Khan, N. et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169, 1984-1992 (2002). (Pubitemid 34857662)
45. Wills, M. R. et al. Identification of naive or antigen-experienced human CD8+ T cells by expression of costimulation and chemokine receptors: analysis of the human cytomegalovirus-specific CD8+ T cell response. J. Immunol. 168, 5455-5464 (2002). (Pubitemid 34556123)
46. Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111-2124 (2008).
47. Hoare, M. et al. CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection. J. Hepatol. 53, 252-260 (2010).
48. Koch, S. et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing 5, 6 (2008).
49. Mountz, J. D., Wu, J., Zhou, T. & Hsu, H. C. Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence. Immunol. Rev. 160, 19-30 (1997). (Pubitemid 28021363)
50. Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212-4222 (2003). (Pubitemid 37021749)
51. Davis, T. et al. Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38αMAPK inhibitors in Werner syndrome cells. Bioorg. Med. Chem. Lett. 17, 6832-6835 (2007). (Pubitemid 350061312)
52. Ono, K. & Han, J. The p38 signal transduction pathway: activation and function. Cell Signal. 12, 1-13 (2000). (Pubitemid 30017963)
53. Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205-2213 (1998). (Pubitemid 29028493)
54. Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206-210 (2009).
55. Urbani, S. et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80, 11398-11403 (2006). (Pubitemid 44706581)
56. Nakamoto, N. et al. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313 (2009).
57. Islam, S. A. et al. Persistence of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte clones in a subject with rapid disease progression. J. Virol. 75, 4907-4911 (2001). (Pubitemid 32381534)
58. Lee, P. P. et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nature Med. 5, 677-685 (1999). (Pubitemid 29289432)
59. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., Van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911-4927 (2003). (Pubitemid 36402840)
60. Richter, K., Agnellini, P. & Oxenius, A. On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int. Immunol. 22, 13-23 (2010).
61. Klenerman, P. & Hill, A. T cells and viral persistence: lessons from diverse infections. Nature Immunol. 6, 873-879 (2005). (Pubitemid 43090441)
62. Sharpe, A. H., Wherry, E. J., Ahmed, R. & Freeman, G. J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunol. 8, 239-245 (2007). (Pubitemid 46745373)
63. Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N. & Ahmed, R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl Acad. Sci. USA 101, 16004-16009 (2004). (Pubitemid 39507917)
64. Shin, H., Blackburn, S. D., Blattman, J. N. & Wherry, E. J. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941-949 (2007). (Pubitemid 46631621)
65. Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281-2292 (2006). (Pubitemid 44498363)
66. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Med. 12, 1198-1202 (2006). (Pubitemid 44527357)
67. Boni, C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215-4225 (2007). (Pubitemid 46586915)
68. Boettler, T. et al. Expression of the interleukin-7 receptor α chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J. Virol. 80, 3532-3540 (2006).
69. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670-684 (2007). (Pubitemid 47615511)
70. Kaufmann, D. E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nature Immunol. 8, 1246-1254 (2007). (Pubitemid 350011764)
71. Jones, R. B. et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205, 2763-2779 (2008).
72. Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175-2186 (2010).
73. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187-2194 (2010).
74. Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474-481 (2010).
75. Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The B7 family revisited. Annu. Rev. Immunol. 23, 515-548 (2005). (Pubitemid 40563179)
76. Czesnikiewicz-Guzik, M. et al. T cell subset-specific susceptibility to aging. Clin. Immunol. 127, 107-118 (2008).
77. Fann, M. et al. Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol. Rev. 205, 190-206 (2005). (Pubitemid 40780186)
78. Cao, J. N., Gollapudi, S., Sharman, E. H., Jia, Z. & Gupta, S. Age-related alterations of gene expression patterns in human CD8+ T cells. Aging Cell 9, 19-31 (2010).
79. Sharpe, A. H. & Freeman, G. J. The B7-CD28 superfamily. Nature Rev. Immunol. 2, 116-126 (2002). (Pubitemid 37323235)
80. Rudd, C. E., Taylor, A. & Schneider, H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev. 229, 12-26 (2009).
81. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543-9553 (2005). (Pubitemid 41507854)
82. Henson, S. M. et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 113, 6619-6628 (2009).
83. Ouyang, Q. et al. Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp. Gerontol. 38, 911-920 (2003). (Pubitemid 36952673)
84. Voehringer, D., Koschella, M. & Pircher, H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100, 3698-3702 (2002). (Pubitemid 35303941)
85. Grayson, J. M., Weant, A. E., Holbrook, B. C. & Hildeman, D. Role of Bim in regulating CD8+ T-cell responses during chronic viral infection. J. Virol. 80, 8627-8638 (2006). (Pubitemid 44384873)
86. Lopes, A. R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835-1845 (2008). (Pubitemid 351632386)
87. Shin, H. et al. A role for the transcriptional repressor BlimP-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309-320 (2009).
88. Angelosanto, J. M. & Wherry, E. J. Transcription factor regulation of CD8+ T-cell memory and exhaustion. Immunol. Rev. 236, 167-175 (2010).
89. Fauce, S. R. et al. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J. Immunol. 181, 7400-7406 (2008).
90. Van De Berg, P. J. et al. Cytomegalovirus infection reduces telomere length of the circulating T cell pool. J. Immunol. 184, 3417-3423 (2010).
91. Lichterfeld, M. et al. Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors. Blood 112, 3679-3687 (2008).
92. Dagarag, M., Evazyan, T., Rao, N. & Effros, R. B. Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J. Immunol. 173, 6303-6311 (2004). (Pubitemid 39487789)
93. Henson, S. M. & Akbar, A. N. KLRG1-more than a marker for T cell senescence. Age 31, 285-291 (2009).
94. Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782-787 (2000). (Pubitemid 30212408)
95. Greenwald, R. J., Latchman, Y. E. & Sharpe, A. H. Negative co-receptors on lymphocytes. Curr. Opin. Immunol. 14, 391-396 (2002). (Pubitemid 34327984)