T cell function in the aged: Lessons learned from animal models

Clinical and Applied Immunology Reviews

Volumn 6, Issue 2, 2006, Pages 73-97

  Linton, Phyllis Jean ^a   Lustgarten, Joseph ^a   Thoman, Marilyn ^a  

^a SIDNEY KIMMEL CANCER CENTER   (United States)

Author keywords

Aging; Cancer; Homeostasis; T cell; T cell expansions; Thymic development

Indexed keywords

ALPHA TOCOPHEROL; ANTIOXIDANT; B7 ANTIGEN; CANCER VACCINE; CD27 ANTIGEN; CD30 ANTIGEN; CD45RA ANTIGEN; CD45RO ANTIGEN; CD69 ANTIGEN; CD86 ANTIGEN; DNA VACCINE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; GAMMA INTERFERON; GROWTH FACTOR; INFLUENZA VACCINE; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 7; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 4 1BB; MONOCLONAL ANTIBODY OX40; SOMATOMEDIN C; T LYMPHOCYTE RECEPTOR; TELOMERASE; TRANSCRIPTION FACTOR; TUMOR ANTIGEN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

AGING; ANTINEOPLASTIC ACTIVITY; CANCER; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; DISEASE PREDISPOSITION; HOMEOSTASIS; HORMONE SUBSTITUTION; HUMAN; IMMUNE RESPONSE; INCIDENCE; INFECTION; INFLUENZA; INNATE IMMUNITY; INVOLUTION; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MORBIDITY; MORTALITY; NONHUMAN; PERIPHERAL LYMPHOCYTE; PRIORITY JOURNAL; REJUVENATION; REVIEW; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; TELOMERE; THYMUS; VACCINATION;

EID: 33748526805     PISSN: 15291049     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.cair.2006.06.001     Document Type: Review

References (213)

1. Boyd E. The weight of the thymus gland in health and in disease. Am J Dis Child 43 (1932) 1162
2. Aspinall R., and Andrew D. Thymic involution in aging. J Clin Immunol 20 (2000) 250-256
3. Taub D.D., and Longo D.L. Insights into thymic aging and regeneration. Immunol Rev 205 (2005) 72-93
4. Allman D., Sambandam A., Kim S., Miller J.P., Pagan A., Well D., et al. Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4 (2003) 168-174
5. Min H., Montecino-Rodriguez E., and Dorshkind K. Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol 173 (2004) 245-250
6. Bhandoola A., Sambandam A., Allman D., Meraz A., and Schwarz B. Early T lineage progenitors: new insights, but old questions remain. J Immunol 171 (2003) 5653-5658
7. Tyan M.L. Impaired thymic regeneration in lethally irradiated mice given bone marrow from aged donors. Proc Soc Exp Biol Med 152 (1976) 33-35
8. Hirokawa K., Sado T., Kubo S., Kamisaku H., and Utsuyama M. Contrasting feature in the repopulation of host-type T cells in the spleens of F1→P and P→F1 radiation bone marrow chimeras. Cell Immunol 103 (1986) 174-182
9. Thoman M.L. The pattern of T lymphocyte differentiation is altered during thymic involution. Mech Ageing Dev 82 (1995) 155-170
10. Aspinall R. Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development. J Immunol 158 (1997) 3037-3045
11. Globerson A. Thymocytopoiesis in aging: the bone marrow-thymus axis. Arch Gerontol Geriatr 24 (1997) 141-155
12. Andrew D., and Aspinall R. Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp Gerontol 37 (2002) 455-463
13. Ortman C.L., Dittmar K.A., Witte P.L., and Le P.T. Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol 14 (2002) 813-822
14. Rodewald H.R., Kretzschmar K., Swat W., and Takeda S. Intrathymically expressed c-kit ligand (stem cell factor) is a major factor driving expansion of very immature thymocytes in vivo. Immunity 3 (1995) 313-319
15. Rodewald H.R., Ogawa M., Haller C., Waskow C., and DiSanto J.P. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma chain is essential for repertoire formation. Immunity 6 (1997) 265-272
16. Peschon J.J., Morrissey P.J., Grabstein K.H., Ramsdell F.J., Maraskovsky E., Gliniak B.C., et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180 (1994) 1955-1960
17. Kim K., Lee C.K., Sayers T.J., Muegge K., and Durum S.K. The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J Immunol 160 (1998) 5735-5741
18. von Freeden-Jeffry U., Vieira P., Lucian L.A., McNeil T., Burdach S.E., and Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181 (1995) 1519-1526
19. Andrew D., and Aspinall R. Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol 166 (2001) 1524-1530
20. Haynes B.F., Markert M.L., Sempowski G.D., Patel D.D., and Hale L.P. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 18 (2000) 529-560
21. Phillips J.A., Brondstetter T.I., English C.A., Lee H.E., Virts E.L., and Thoman M.L. IL-7 gene therapy in aging restores early thymopoiesis without reversing involution. J Immunol 173 (2004) 4867-4874
22. Greenstein B.D., Fitzpatrick F.T., Adcock I.M., Kendall M.D., and Wheeler M.J. Reappearance of the thymus in old rats after orchidectomy: inhibition of regeneration by testosterone. J Endocrinol 110 (1986) 417-422
23. Haynes B.F., Sempowski G.D., Wells A.F., and Hale L.P. The human thymus during aging. Immunol Res 22 (2000) 253-261
24. Quaglino D., Capri M., Bergamini G., Euclidi E., Zecca L., Franceschi C., et al. Age-dependent remodeling of rat thymus. Morphological and cytofluorimetric analysis from birth up to one year of age. Eur J Cell Biol 76 (1998) 156-166
25. Steinmann G.G., Klaus B., and Muller-Hermelink H.K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol 22 (1985) 563-575
26. Scollay R.G., Butcher E.C., and Weissman I.L. Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10 (1980) 210-218
27. Hartwig M., and Steinmann G. On a causal mechanism of chronic thymic involution in man. Mech Ageing Dev 75 (1994) 151-156
28. Douek D.C., McFarland R.D., Keiser P.H., Gage E.A., Massey J.M., Haynes B.F., et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396 (1998) 690-695
29. Poulin J.F., Viswanathan M.N., Harris J.M., Komanduri K.V., Wieder E., Ringuette N., et al. Direct evidence for thymic function in adult humans. J Exp Med 190 (1999) 479-486
30. Lerner A., Yamada T., and Miller R.A. Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur J Immunol 19 (1989) 977-982
31. Ernst D.N., Hobbs M.V., Torbett B.E., Glasebrook A.L., Rehse M.A., Bottomly K., et al. Differences in the expression profiles of CD45RB, Pgp-1, and 3G11 membrane antigens and in the patterns of lymphokine secretion by splenic CD4+ T cells from young and aged mice. J Immunol 145 (1990) 1295-1302
32. Fagnoni F.F., Vescovini R., Passeri G., Bologna G., Pedrazzoni M., Lavagetto G., et al. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95 (2000) 2860-2868
33. Utsuyama M., Hirokawa K., Kurashima C., Fukayama M., Inamatsu T., Suzuki K., et al. Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech Ageing Dev 63 (1992) 57-68
34. Miller R.A. The aging immune system: primer and prospectus. Science 273 (1996) 70-74
35. Posnett D.N., Sinha R., Kabak S., and Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med 179 (1994) 609-618
36. Callahan J.E., Kappler J.W., and Marrack P. Unexpected expansions of CD8-bearing cells in old mice. J Immunol 151 (1993) 6657-6669
37. LeMaoult J., Messaoudi I., Manavalan J.S., Potvin H., Nikolich-Zugich D., Dyall R., et al. Age-related dysregulation in CD8 T cell homeostasis: kinetics of a diversity loss. J Immunol 165 (2000) 2367-2373
38. Effros R.B., and Pawelec G. Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion?. Immunol Today 18 (1997) 450-454
39. Surh C.D., and Sprent J. Regulation of mature T cell homeostasis. Semin Immunol 17 (2005) 183-191
40. Jameson S.C. T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin Immunol 17 (2005) 231-237
41. Murasko D.M., and Jiang J. Response of aged mice to primary virus infections. Immunol Rev 205 (2005) 285-296
42. Tumpey T.M., Lu X., Morken T., Zaki S.R., and Katz J.M. Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans. J Virol 74 (2000) 6105-6116
43. Min B., McHugh R., Sempowski G.D., Mackall C., Foucras G., and Paul W.E. Neonates support lymphopenia-induced proliferation. Immunity 18 (2003) 131-140
44. Messaoudi I., Lemaoult J., Guevara-Patino J.A., Metzner B.M., and Nikolich-Zugich J. Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med 200 (2004) 1347-1358
45. Kieper W.C., Burghardt J.T., and Surh C.D. A role for TCR affinity in regulating naive T cell homeostasis. J Immunol 172 (2004) 40-44
46. Murali-Krishna K., and Ahmed R. Cutting edge: naive T cells masquerading as memory cells. J Immunol 165 (2000) 1733-1737
47. Tanchot C., Le Campion A., Leaument S., Dautigny N., and Lucas B. Naive CD4(+) lymphocytes convert to anergic or memory-like cells in T cell-deprived recipients. Eur J Immunol 31 (2001) 2256-2265
48. Oehen S., and Brduscha-Riem K. Naive cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: a pitfall for T cell memory studies?. Eur J Immunol 29 (1999) 608-614
49. Hu H.M., Poehlein C.H., Urba W.J., and Fox B.A. Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res 62 (2002) 3914-3919
50. Zhang X., Fujii H., Kishimoto H., LeRoy E., Surh C.D., and Sprent J. Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells. J Exp Med 195 (2002) 283-293
51. Valenzuela H.F., and Effros R.B. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 105 (2002) 117-125
52. Schwab R., Szabo P., Manavalan J.S., Weksler M.E., Posnett D.N., Pannetier C., et al. Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 158 (1997) 4493-4499
53. Chamberlain W.D., Falta M.T., and Kotzin B.L. Functional subsets within clonally expanded CD8(+) memory T cells in elderly humans. Clin Immunol 94 (2000) 160-172
54. Ku C.C., Kappler J., and Marrack P. The growth of the very large CD8+ T cell clones in older mice is controlled by cytokines. J Immunol 166 (2001) 2186-2193
55. Saurwein-Teissl M., Lung T.L., 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 168 (2002) 5893-5899
56. Dunne P.J., Faint J.M., Gudgeon N.H., Fletcher J.M., Plunkett F.J., Soares M.V., et al. Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100 (2002) 933-940
57. Posnett D.N., Edinger J.W., Manavalan J.S., Irwin C., and Marodon G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. Int Immunol 11 (1999) 229-241
58. van Baarle D., Tsegaye A., Miedema F., and Akbar A. Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system. Immunol Lett 97 (2005) 19-29
59. Clambey E.T., van Dyk L.F., Kappler J.W., and Marrack P. Non-malignant clonal expansions of CD8+ memory T cells in aged individuals. Immunol Rev 205 (2005) 170-189
60. Looney R.J., Falsey A., Campbell D., Torres A., Kolassa J., Brower C., et al. Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol 90 (1999) 213-219
61. Khan N., Shariff N., Cobbold M., Bruton R., Ainsworth J.A., Sinclair A.J., et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169 (2002) 1984-1992
62. van Lier R.A., ten Berge I.J., and Gamadia L.E. Human CD8(+) T-cell differentiation in response to viruses. Nat Rev Immunol 3 (2003) 931-939
63. Li F., Yarilin D.A., Valiando J., Ronco A., Weksler M.E., Szabo P., et al. Tumor antigen drives a persistent oligoclonal expansion of CD8+ T cells in aged mice. Eur J Immunol 32 (2002) 1650-1658
64. Sandau M.M., Schluns K.S., Lefrancois L., and Jameson S.C. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells. J Immunol 173 (2004) 6537-6541
65. Murakami M., Sakamoto A., Bender J., Kappler J., and Marrack P. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc Natl Acad Sci U S A 99 (2002) 8832-8837
66. Kamimura D., Ueda N., Sawa Y., Hachida S., Atsumi T., Nakagawa T., et al. Evidence of a novel IL-2/15R beta-targeted cytokine involved in homeostatic proliferation of memory CD8+ T cells. J Immunol 173 (2004) 6041-6049
67. Hathcock K.S., Jeffrey Chiang Y., and Hodes R.J. In vivo regulation of telomerase activity and telomere length. Immunol Rev 205 (2005) 104-113
68. Pawelec G., Akbar A., Caruso C., Effros R., Grubeck-Loebenstein B., and Wikby A. Is immunosenescence infectious?. Trends Immunol 25 (2004) 406-410
69. Vallejo A.N., Weyand C.M., and Goronzy J.J. T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 10 (2004) 119-124
70. Ouyang Q., Wagner W.M., Walter S., Muller C.A., Wikby A., Aubert G., et al. An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein-Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness. Mech Ageing Dev 124 (2003) 477-485
71. Voehringer D., Koschella M., and Pircher H. Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100 (2002) 3698-3702
72. Voehringer D., Blaser C., Brawand P., Raulet D.H., Hanke T., and Pircher H. Viral infections induce abundant numbers of senescent CD8 T cells. J Immunol 167 (2001) 4838-4843
73. Ouyang Q., Wagner W.M., Voehringer D., Wikby A., Klatt T., Walter S., et al. Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol 38 (2003) 911-920
74. 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 99 (2002) 2505-2511
75. Migueles S.A., Laborico A.C., Shupert W.L., Sabbaghian M.S., Rabin R., Hallahan C.W., et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3 (2002) 1061-1068
76. Appay V., Nixon D.F., Donahoe S.M., Gillespie G.M., Dong T., King A., et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192 (2000) 63-75
77. Effros R.B., Dagarag M., Spaulding C., and Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205 (2005) 147-157
78. Linton P.J., Haynes L., Klinman N.R., and Swain S.L. Antigen-independent changes in naive CD4 T cells with aging. J Exp Med 184 (1996) 1891-1900
79. Linton P.J., Haynes L., Tsui L., Zhang X., and Swain S. From naive to effector-alterations with aging. Immunol Rev 160 (1997) 9-18
80. Haynes L., Eaton S.M., Burns E.M., Randall T.D., and Swain S.L. Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen. J Exp Med 201 (2005) 845-851
81. Flescher E., Ledbetter J.A., Schieven G.L., Vela-Roch N., Fossum D., Dang H., et al. Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction. J Immunol 153 (1994) 4880-4889
82. Lohmiller J.J., Roellich K.M., Toledano A., Rabinovitch P.S., Wolf N.S., and Grossmann A. Aged murine T-lymphocytes are more resistant to oxidative damage due to the predominance of the cells possessing the memory phenotype. J Gerontol A Biol Sci Med Sci 51 (1996) B132-B140
83. Ames B.N., Shigenaga M.K., and Hagen T.M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 90 (1993) 7915-7922
84. Garcia G.G., and Miller R.A. Single-cell analyses reveal two defects in peptide-specific activation of naive T cells from aged mice. J Immunol 166 (2001) 3151-3157
85. Miller R.A., Garcia G., Kirk C.J., and Witkowski J.M. Early activation defects in T lymphocytes from aged mice. Immunol Rev 160 (1997) 79-90
86. Miller R.A., Berger S.B., Burke D.T., Galecki A., Garcia G.G., Harper J.M., et al. T cells in aging mice: genetic, developmental, and biochemical analyses. Immunol Rev 205 (2005) 94-103
87. Haynes L., Eaton S.M., Burns E.M., Randall T.D., and Swain S.L. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci U S A 100 (2003) 15053-15058
88. Li S.P., Cai Z., Shi W., Brunmark A., Jackson M., and Linton P.J. Early antigen-specific response by naive CD8 T cells is not altered with aging. J Immunol 168 (2002) 6120-6127
89. Norian L.A., and Allen P.M. No intrinsic deficiencies in CD8+ T cell-mediated antitumor immunity with aging. J Immunol 173 (2004) 835-844
90. Linton P.J., Li S.P., Zhang Y., Bautista B., Huynh Q., and Trinh T. Intrinsic versus environmental influences on T-cell responses in aging. Immunol Rev 205 (2005) 207-219
91. Po J.L., Gardner E.M., Anaraki F., Katsikis P.D., and Murasko D.M. Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev 123 (2002) 1167-1181
92. Couch R.B., Kasel J.A., Glezen W.P., Cate T.R., Six H.R., Taber L.H., et al. Influenza: its control in persons and populations. J Infect Dis 153 (1986) 431-440
93. Effros R.B., and Walford R.L. The immune response of aged mice to influenza: diminished T-cell proliferation, interleukin 2 production and cytotoxicity. Cell Immunol 81 (1983) 298-305
94. Khanolkar A., Fuller M.J., and Zajac A.J. T cell responses to viral infections: lessons from lymphocytic choriomeningitis virus. Immunol Res 26 (2002) 309-321
95. Kapasi Z.F., Murali-Krishna K., McRae M.L., and Ahmed R. Defective generation but normal maintenance of memory T cells in old mice. Eur J Immunol 32 (2002) 1567-1573
96. Kris R.M., Yetter R.A., Cogliano R., Ramphal R., and Small P.A. Passive serum antibody causes temporary recovery from influenza virus infection of the nose, trachea and lung of nude mice. Immunology 63 (1988) 349-353
97. Lukacher A.E., Braciale V.L., and Braciale T.J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160 (1984) 814-826
98. Bender B.S., Taylor S.F., Zander D.S., and Cottey R. Pulmonary immune response of young and aged mice after influenza challenge. J Lab Clin Med 126 (1995) 169-177
99. McElhaney J.E., Upshaw C.M., Hooton J.W., Lechelt K.E., and Meneilly G.S. Responses to influenza vaccination in different T-cell subsets: a comparison of healthy young and older adults. Vaccine 16 (1998) 1742-1747
100. Mbawuike I.N., Lange A.R., and Couch R.B. Diminished influenza A virus-specific MHC class I-restricted cytotoxic T lymphocyte activity among elderly persons. Viral Immunol 6 (1993) 55-64
101. Bender B.S., Johnson M.P., and Small P.A. Influenza in senescent mice: impaired cytotoxic T-lymphocyte activity is correlated with prolonged infection. Immunology 72 (1991) 514-519
102. Bernstein E., Kaye D., Abrutyn E., Gross P., Dorfman M., and Murasko D.M. Immune response to influenza vaccination in a large healthy elderly population. Vaccine 17 (1999) 82-94
103. Webster R.G. Immunity to influenza in the elderly. Vaccine 18 (2000) 1686-1689
104. Deng Y., Jing Y., Campbell A.E., and Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol 172 (2004) 3437-3446
105. Kang I., Hong M.S., Nolasco H., Park S.H., Dan J.M., Choi J.Y., et al. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J Immunol 173 (2004) 673-681
106. Engelhard V.H., Bullock T.N., Colella T.A., Sheasley S.L., and Mullins D.W. Antigens derived from melanocyte differentiation proteins: self-tolerance, autoimmunity, and use for cancer immunotherapy. Immunol Rev 188 (2002) 136-146
107. Cuenca A., Cheng F., Wang H., Brayer J., Horna P., Gu L., et al. Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res 63 (2003) 9007-9015
108. Staveley-O'Carroll K., Sotomayor E., Montgomery J., Borrello I., Hwang L., Fein S., et al. Induction of antigen-specific T cell anergy: an early event in the course of tumor progression. Proc Natl Acad Sci U S A 95 (1998) 1178-1183
109. Chatenoud L., Salomon B., and Bluestone J.A. Suppressor T cells-they're back and critical for regulation of autoimmunity!. Immunol Rev 182 (2001) 149-163
110. Tang Q., Henriksen K.J., Bi M., Finger E.B., Szot G., Ye J., et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199 (2004) 1455-1465
111. Kono K., Kawaida H., Takahashi A., Sugai H., Mimura K., Miyagawa N., et al. CD4(+)CD25(high) regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother (2005) 1-8
112. Yamaguchi T., and Sakaguchi S. Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16 (2006) 115-123
113. Gregg R., Smith C.M., Clark F.J., Dunnion D., Khan N., et al. The number of human peripheral blood CD4+ CD25 high regulatory T cells increases with age. Clin Exp Immunol 140 (2005) 540-546
114. Sprent J. Central tolerance of T cells. Int Rev Immunol 13 (1995) 95-105
115. Starr T.K., Jameson S.C., and Hogquist K.A. Positive and negative selection of T cells. Annu Rev Immunol 21 (2003) 139-176
116. Kappler J.W., Roehm N., and Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 49 (1987) 273-280
117. Kisielow P., Bluthmann H., Staerz U.D., Steinmetz M., and von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333 (1988) 742-746
118. Surh C.D., and Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372 (1994) 100-103
119. Sha W.C., Nelson C.A., Newberry R.D., Kranz D.M., Russell J.H., and Loh D.Y. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature 335 (1988) 271-274
120. Redmond W.L., and Sherman L.A. Peripheral tolerance of CD8 T lymphocytes. Immunity 22 (2005) 275-284
121. Brennan P.J., Saouaf S.J., Greene M.I., and Shen Y. Anergy and suppression as coexistent mechanisms for the maintenance of peripheral T cell tolerance. Immunol Res 27 (2003) 295-302
122. Van den Eynde B.J., and Boon T. Tumor antigens recognized by T lymphocytes. Int J Clin Lab Res 27 (1997) 81-86
123. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254 (1991) 1643-1647
124. Lurquin C., Van Pel A., Mariame B., De Plaen E., Szikora J.P., Janssens C., et al. Structure of the gene of tum- transplantation antigen P91A: the mutated exon encodes a peptide recognized with Ld by cytolytic T cells. Cell 58 (1989) 293-303
125. Valmori D., Levy F., Miconnet I., Zajac P., Spagnoli G.C., Rimoldi D., et al. Induction of potent antitumor CTL responses by recombinant vaccinia encoding a melan-A peptide analogue. J Immunol 164 (2000) 1125-1131
126. El-Shami K.M., Tirosh B., Popovic D., Carmon L., Tzehoval E., Vadai E., et al. Induction of antitumor immunity by proteasome-inhibited syngeneic fibroblasts pulsed with a modified TAA peptide. Int J Cancer 85 (2000) 236-242
127. Goldrath A.W., and Bevan M.J. Selecting and maintaining a diverse T-cell repertoire. Nature 402 (1999) 255-262
128. Geiger T., Gooding L.R., and Flavell R.A. T-cell responsiveness to an oncogenic peripheral protein and spontaneous autoimmunity in transgenic mice. Proc Natl Acad Sci U S A 89 (1992) 2985-2989
129. Hausmann S., Martin M., Gauthier L., and Wucherpfennig K.W. Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition. J Immunol 162 (1999) 338-344
130. Cordaro T.A., de Visser K.E., Tirion F.H., Schumacher T.N., and Kruisbeek A.M. Can the low-avidity self-specific T cell repertoire be exploited for tumor rejection?. J Immunol 168 (2002) 651-660
131. Kawai K., and Ohashi P.S. Immunological function of a defined T-cell population tolerized to low-affinity self antigens. Nature 374 (1995) 68-69
132. Theobald M., Biggs J., Hernandez J., Lustgarten J., Labadie C., and Sherman L.A. Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes. J Exp Med 185 (1997) 833-841
133. Mukherjee P., Ginardi A.R., Madsen C.S., Sterner C.J., Adriance M.C., Tevethia M.J., et al. Mice with spontaneous pancreatic cancer naturally develop MUC-1-specific CTLs that eradicate tumors when adoptively transferred. J Immunol 165 (2000) 3451-3460
134. Sandberg J.K., Franksson L., Sundback J., Michaelsson J., Petersson M., Achour A., et al. T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity. J Immunol 165 (2000) 25-33
135. Kersh G.J., and Allen P.M. Essential flexibility in the T-cell recognition of antigen. Nature 380 (1996) 495-498
136. Jacobsen M., Cepok S., Oertel W.H., Sommer N., and Hemmer B. New approaches to dissect degeneracy and specificity in T cell antigen recognition. J Mol Med 79 (2001) 358-367
137. Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19 (1998) 395-404
138. Morgan D.J., Kreuwel H.T., Fleck S., Levitsky H.I., Pardoll D.M., and Sherman L.A. Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. J Immunol 160 (1998) 643-651
139. de Visser K.E., Cordaro T.A., Kioussis D., Haanen J.B., Schumacher T.N., and Kruisbeek A.M. Tracing and characterization of the low-avidity self-specific T cell repertoire. Eur J Immunol 30 (2000) 1458-1468
140. Miller R.A., and Chrisp C. T cell subset patterns that predict resistance to spontaneous lymphoma, mammary adenocarcinoma, and fibrosarcoma in mice. J Immunol 169 (2002) 1619-1625
141. Provinciali M., Smorlesi A., Donnini A., Bartozzi B., and Amici A. Low effectiveness of DNA vaccination against HER-2/neu in ageing. Vaccine 21 (2003) 843-848
142. Lustgarten J., Dominguez A.L., and Thoman M. Aged mice develop protective antitumor immune responses with appropriate costimulation. J Immunol 173 (2004) 4510-4515
143. Flood P.M., Liu X., Alexander R., Schreiber H., and Haque S. Loss of resistance to a highly immunogenic tumor with age corresponds to the decline of CD8 T cell activity. J Immunother 21 (1998) 307-316
144. van der Merwe P.A., and Davis S.J. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 21 (2003) 659-684
145. Lenschow D.J., Walunas T.L., and Bluestone J.A. CD28/B7 system of T cell costimulation. Annu Rev Immunol 14 (1996) 233-258
146. Wingren A.G., Parra E., Varga M., Kalland T., Sjogren H.O., Hedlund G., et al. T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. Crit Rev Immunol 15 (1995) 235-253
147. Screaton G., and Xu X.N. T cell life and death signalling via TNF-receptor family members. Curr Opin Immunol 12 (2000) 316-322
148. Weinberg A.D. OX40: targeted immunotherapy-implications for tempering autoimmunity and enhancing vaccines. Trends Immunol 23 (2002) 102-109
149. Wilcox R.A., Flies D.B., Zhu G., Johnson A.J., Tamada K., Chapoval A.I., et al. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 109 (2002) 651-659
150. Pan P.Y., Zang Y., Weber K., Meseck M.L., and Chen S.H. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 6 (2002) 528-536
151. Guinn B.A., DeBenedette M.A., Watts T.H., and Berinstein N.L. 4-1BBL cooperates with B7-1 and B7-2 in converting a B cell lymphoma cell line into a long-lasting antitumor vaccine. J Immunol 162 (1999) 5003-5010
152. Bansal-Pakala P., and Croft M. Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). J Immunol 169 (2002) 5005-5009
153. Sambhara S., Kurichh A., Miranda R., Tamane A., Arpino R., James O., et al. Enhanced immune responses and resistance against infection in aged mice conferred by Flu-ISCOMs vaccine correlate with up-regulation of costimulatory molecule CD86. Vaccine 16 (1998) 1698-1704
154. Thoman M.L., and Weigle W.O. Lymphokines and aging: interleukin-2 production and activity in aged animals. J Immunol 127 (1981) 2102-2106
155. Thoman M.L. Role of interleukin-2 in the age-related impairment of immune function. J Am Geriatr Soc 33 (1985) 781-787
156. Thoman M., and Weigle W.O. Age-associated changes in the synthesis and function of cytokines. In: Goidl E.A. (Ed). Aging and the Immune Response: Cellular and Humoral Aspects (1987), Marcel Dekker, Inc, New York, NY 199-223
157. Haynes L., Linton P.J., Eaton S.M., Tonkonogy S.L., and Swain S.L. Interleukin 2, but not other common gamma 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 (1999) 1013-1024
158. Haynes L., Eaton S.M., Burns E.M., Rincon M., and Swain S.L. Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J Immunol 172 (2004) 5194-5199
159. Higgins D.A., Carlson J.R., and Van Nest G. MF59 adjuvant enhances the immunogenicity of influenza vaccine in both young and old mice. Vaccine 14 (1996) 478-484
160. Manning B.M., Enioutina E.Y., Visic D.M., Knudson A.D., and Daynes R.A. CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp Gerontol 37 (2001) 107-126
161. Sambhara S., Kurichh A., Miranda R., James O., Underdown B., Klein M., et al. Severe impairment of primary but not memory responses to influenza viral antigens in aged mice: costimulation in vivo partially reverses impaired primary immune responses. Cell Immunol 210 (2001) 1-4
162. Dong L., Mori I., Hossain M.J., Liu B., and Kimura Y. An immunostimulatory oligodeoxynucleotide containing a cytidine-guanosine motif protects senescence-accelerated mice from lethal influenza virus by augmenting the T helper type 1 response. J Gen Virol 84 (2003) 1623-1628
163. Guebre-Xabier M., Hammond S.A., Ellingsworth L.R., and Glenn G.M. Immunostimulant patch enhances immune responses to influenza virus vaccine in aged mice. J Virol 78 (2004) 7610-7618
164. Hayek M.G., Meydani S.N., Meydani M., and Blumberg J.B. Age differences in eicosanoid production of mouse splenocytes: effects on mitogen-induced T-cell proliferation. J Gerontol 49 (1994) B197-B207
165. Hayek M.G., Mura C., Wu D., Beharka A.A., Han S.N., Paulson K.E., et al. Enhanced expression of inducible cyclooxygenase with age in murine macrophages. J Immunol 159 (1997) 2445-2451
166. Wu D., Marko M., Claycombe K., Paulson K.E., and Meydani S.N. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. J Biol Chem 278 (2003) 10983-10992
167. Meydani S.N., Barklund M.P., Liu S., Meydani M., Miller R.A., Cannon J.G., et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 52 (1990) 557-563
168. Meydani S.N., Meydani M., Verdon C.P., Shapiro A.A., Blumberg J.B., and Hayes K.C. Vitamin E supplementation suppresses prostaglandin E1(2) synthesis and enhances the immune response of aged mice. Mech Ageing Dev 34 (1986) 191-201
169. Roth A., Yssel H., Pene J., Chavez E.A., Schertzer M., Lansdorp P.M., et al. Telomerase levels control the lifespan of human T lymphocytes. Blood 102 (2003) 849-857
170. Vaziri H., and Benchimol S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 8 (1998) 279-282
171. Hooijberg E., Ruizendaal J.J., Snijders P.J., Kueter E.W., Walboomers J.M., and Spits H. Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 165 (2000) 4239-4245
172. Luiten R.M., Pene J., Yssel H., and Spits H. Ectopic hTERT expression extends the life span of human CD4+ helper and regulatory T-cell clones and confers resistance to oxidative stress-induced apoptosis. Blood 101 (2003) 4512-4519
173. Dagarag M., Evazyan T., Rao N., and 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 (2004) 6303-6311
174. Li Y., Zhi W., Wareski P., and Weng N.P. IL-15 activates telomerase and minimizes telomere loss and may preserve the replicative life span of memory CD8+ T cells in vitro. J Immunol 174 (2005) 4019-4024
175. Masoro E.J. Overview of caloric restriction and ageing. Mech Ageing Dev 126 (2005) 913-922
176. Guayerbas N., Puerto M., Alvarez P., and de la Fuente M. Improvement of the macrophage functions in prematurely ageing mice by a diet supplemented with thiolic antioxidants. Cell Mol Biol (Noisy-le-grand) 50 (2004) Online Pub: OL677-8150
177. Bunout D., Barrera G., Hirsch S., Gattas V., de la Maza M.P., Haschke F., et al. Effects of a nutritional supplement on the immune response and cytokine production in free-living Chilean elderly. JPEN J Parenter Enteral Nutr 28 (2004) 348-354
178. Meydani S.N., Han S.N., and Wu D. Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immunol Rev 205 (2005) 269-284
179. Ahmed T., Marko M., Wu D., Chung H., Huber B., and Meydani S.N. Vitamin E supplementation reverses the age-associated decrease in effective immune synapse formation in CD4+ T cells. Ann N Y Acad Sci 1031 (2004) 412-414
180. Savino W., Postel-Vinay M.C., Smaniotto S., and Dardenne M. The thymus gland: a target organ for growth hormone. Scand J Immunol 55 (2002) 442-452
181. Kay M.M., Mendoza J., Diven J., Denton T., Union N., and Lajiness M. Age-related changes in the immune system of mice of eight medium and long-lived strains and hybrids. I. Organ, cellular, and activity changes. Mech Ageing Dev 11 (1979) 295-346
182. Hirokawa K. The thymus and aging. In: TMaE Y, editor. Comprehensive immunology: immunoregulation in aging. New York, 1977. pp. 51.
183. Santisteban G.A. The growth and involution of lymphatic tissue and its interrelationships to aging and to the growth of the adrenal glands and sex organs in CBA mice. Anat Rec 136 (1960) 117-126
184. Hirokawa K., Albright J.W., and Makinodan T. Restoration of impaired immune functions in aging animals. II. Effect of syngeneic thymus and bone marrow grafts. Clin Immunol Immunopathol 5 (1976) 371-376
185. Hirokawa K., Sato K., and Makinodan T. Influence of age of thymic grafts on the differentiation of T cells in nude mice. Clin Immunol Immunopathol 24 (1982) 251-262
186. Hakim F.T., Memon S.A., Cepeda R., Jones E.C., Chow C.K., Kasten-Sportes C., et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115 (2005) 930-939
187. Hong R., Schulte-Wissermann H., Jarrett-Toth E., Horowitz S.D., and Manning D.D. Transplantation of cultured thymic fragments. II. Results in nude mice. J Exp Med 149 (1979) 398-415
188. Gill J., Malin M., Hollander G.A., and Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3 (2002) 635-642
189. Gill J., Malin M., Sutherland J., Gray D., Hollander G., and Boyd R. Thymic generation and regeneration. Immunol Rev 195 (2003) 28-50
190. Min B., Foucras G., Meier-Schellersheim M., and Paul W.E. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci U S A 101 (2004) 3874-3879
191. Sharp A., Kukulansky T., and Globerson A. In vitro analysis of age-related changes in the developmental potential of bone marrow thymocyte progenitors. Eur J Immunol 20 (1990) 2541-2546
192. Eren R., Globerson A., Abel L., and Zharhary D. Quantitative analysis of bone marrow thymic progenitors in young and aged mice. Cell Immunol 127 (1990) 238-246
193. Hirokawa K., Kubo S., Utsuyama M., Kurashima C., and Sado T. Age-related change in the potential of bone marrow cells to repopulate the thymus and splenic T cells in mice. Cell Immunol 100 (1986) 443-451
194. Sudo K., Ema H., Morita Y., and Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192 (2000) 1273-1280
195. Yuan R., Astle C.M., Chen J., and Harrison D.E. Genetic regulation of hematopoietic stem cell exhaustion during development and growth. Exp Hematol 33 (2005) 243-250
196. Olsen N.J., and Kovacs W.J. Effects of androgens on T and B lymphocyte development. Immunol Res 23 (2001) 281-288
197. Windmill K.F., and Lee V.W. Effects of castration on the lymphocytes of the thymus, spleen and lymph nodes. Tissue Cell 30 (1998) 104-111
198. Windmill K.F., and Lee V.W. Influences of surgical castration on the thymus of male rats. J Reprod Immunol 44 (1999) 29-39
199. Pejcic-Karapetrovic B., Kosec D., and Leposavic G. Differential effects of male and female gonadal hormones on the intrathymic T cell maturation. Dev Immunol 8 (2001) 305-317
200. Olsen N.J., Olson G., Viselli S.M., Gu X., and Kovacs W.J. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142 (2001) 1278-1283
201. Islander U., Erlandsson M.C., Hasseus B., Jonsson C.A., Ohlsson C., Gustafsson J.A., et al. Influence of oestrogen receptor alpha and beta on the immune system in aged female mice. Immunology 110 (2003) 149-157
202. Burgess W., Liu Q., Zhou J., Tang Q., Ozawa A., VanHoy R., et al. The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I. Neuroimmunomodulation 6 (1999) 56-68
203. Koo G.C., Huang C., Camacho R., Trainor C., Blake J.T., Sirotina-Meisher A., et al. Immune enhancing effect of a growth hormone secretagogue. J Immunol 166 (2001) 4195-4201
204. Welniak L.A., Sun R., and Murphy W.J. The role of growth hormone in T-cell development and reconstitution. J Leukoc Biol 71 (2002) 381-387
205. Kelley K.W., Brief S., Westly H.J., Novakofski J., Bechtel P.J., Simon J., et al. GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci U S A 83 (1986) 5663-5667
206. Montecino-Rodriguez E., Clark R., and Dorshkind K. Effects of insulin-like growth factor administration and bone marrow transplantation on thymopoiesis in aged mice. Endocrinology 139 (1998) 4120-4126
207. Tian Y.M., Zhang G.Y., and Dai Y.R. Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice. Immunol Lett 88 (2003) 101-104
208. El-Sokkary G.H., Reiter R.J., and Abdel-Ghaffar S. Melatonin supplementation restores cellular proliferation and DNA synthesis in the splenic and thymic lymphocytes of old rats. Neuro Endocrinol Lett 24 (2003) 215-223
209. Oner H., Kus I., Oner J., Ogeturk M., Ozan E., and Ayar A. Possible effects of melatonin on thymus gland after pinealectomy in rats. Neuro Endocrinol Lett 25 (2004) 115-118
210. Tian Y.M., Li P.P., Jiang X.F., Zhang G.Y., and Dai Y.R. Rejuvenation of degenerative thymus by oral melatonin administration and the antagonistic action of melatonin against hydroxyl radical-induced apoptosis of cultured thymocytes in mice. J Pineal Res 31 (2001) 214-221
211. Rezzani R., Rodella L., and Bianchi R. Melatonin antagonises the cyclosporine A immunosuppressive effects in rat thymuses. Int Immunopharmacol 1 (2001) 1615-1619
212. Pido-Lopez J., Imami N., Andrew D., and Aspinall R. Molecular quantitation of thymic output in mice and the effect of IL-7. Eur J Immunol 32 (2002) 2827-2836
213. Mackall C.L., Fry T.J., Bare C., Morgan P., Galbraith A., and Gress R.E. IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 97 (2001) 1491-1497