Mechanisms underlying T cell immunosenescence: Aging and cytomegalovirus infection

Frontiers in Microbiology

Volumn 7, Issue DEC, 2016, Pages

  Tu, Wenjuan ^a   Rao, Sudha ^a  

^a UNIVERSITY OF CANBERRA   (Australia)

Author keywords

Aging; Epigenetic regulation; HCMV infection; Immunosenescence; Naive and memory T cells; Vaccination

Indexed keywords

CD28 ANTIGEN; CD45RA ANTIGEN; EOMESODERMIN; MAMMALIAN TARGET OF RAPAMYCIN; STAPHYLOCOCCUS ENTEROTOXIN B;

AGING; CELL AGING; CHROMATIN IMMUNOPRECIPITATION; CYTOMEGALOVIRUS INFECTION; DNA METHYLATION; GENE EXPRESSION; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL MEMORY; IMMUNOSENESCENCE; IMMUNOTHERAPY; MAJOR HISTOCOMPATIBILITY COMPLEX; MEMORY T LYMPHOCYTE; NONHUMAN; PROTEIN EXPRESSION; REVIEW; T LYMPHOCYTE; VACCINATION;

EID: 85009359407     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2016.02111     Document Type: Review

References (177)

1. Akondy, R. S., Monson, N. D., Miller, J. D., Edupuganti, S., Teuwen, D., Wu, H., et al. (2009). The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 183, 7919-7930. doi: 10.4049/jimmunol.0803903
2. Almanzar, G., Schwaiger, S., Jenewein, B., Keller, M., Herndler-Brandstetter, D., Würzner, R., et al. (2005). Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J. Virol. 79, 3675-3683. doi: 10.1128/JVI.79.6.3675-3683.2005
3. Alonso Arias, R., Moro-García, M. A., Echeverría, A., Solano-Jaurrieta, J. J., Suárez-García, F. M., and López-Larrea, C. (2013). Intensity of the humoral response to cytomegalovirus is associated with the phenotypic and functional status of the immune system. J. Virol. 87, 4486-4495. doi: 10.1128/JVI.02425-12
4. Angelosanto, J. M., and Wherry, E. J. (2010). Transcription factor regulation of CD8+ T-cell memory and exhaustion. Immunol. Rev. 236, 167-175. doi: 10.1111/j.1600-065X.2010.00927.x
5. Appay, V., Dunbar, P. R., Callan, M., Klenerman, P., Gillespie, G. M. A., Papagno, L., et al. (2002). Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379-385. doi: 10.1038/nm0402-379
6. Arai, Y., Martin-Ruiz, C. M., Takayama, M., Abe, Y., Takebayashi, T., Koyasu, S., et al. (2015). Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine 2, 1549-1558. doi: 10.1016/j.ebiom.2015.07.029
7. Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., et al. (2009). mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108-112. doi: 10.1038/nature08155
8. Arens, R., Remmerswaal, E. B. M., Bosch, J. A., and van Lier, R. A. W. (2015). 5th International workshop on CMV and immunosenescence-A shadow of cytomegalovirus infection on immunological memory. Eur. J. Immunol. 45, 954-957. doi: 10.1002/eji.201570044
9. Banerjee, A., Gordon, S. M., Intlekofer, A. M., Paley, M. A., Mooney, E. C., Lindsten, T., et al. (2010). Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J. Immunol. 185, 4988-4992. doi: 10.4049/jimmunol.1002042
10. Barros, S. P., and Offenbacher, S. (2009). Epigenetics: connecting environment and genotype to phenotype and disease. J. Dent. Res. 88, 400-408. doi: 10.1177/0022034509335868
11. Bitmansour, A. D., Douek, D. C., Maino, V. C., and Picker, L. J. (2002). Direct ex vivo analysis of human CD4+ memory T cell activation requirements at the single clonotype level. J. Immunol. 169, 1207-1218. doi: 10.4049/jimmunol.169.3.1207
12. Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., et al. (2009). Coregulation of CD8+ T cell exhaustion during chronic viral infection by multiple inhibitory receptors. Nat. Immunol. 10, 29-37. doi: 10.1038/ni.1679
13. Bollati, V., Schwartz, J., Wright, R., Litonjua, A., Tarantini, L., Suh, H., et al. (2009). Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech. Ageing Dev. 130, 234-239. doi: 10.1016/j.mad.2008.12.003
14. Boraschi, D., and Italiani, P. (2014). Immunosenescence and vaccine failure in the elderly: strategies for improving response. Immunol. Lett. 162, 346-353. doi: 10.1016/j.imlet.2014.06.006
15. Boyd, A., Almeida, J. R., Darrah, P. A., Sauce, D., Seder, R. A., Appay, V., et al. (2015). Pathogen-specific T cell polyfunctionality is a correlate of T cell efficacy and immune protection. PLoS ONE 10:e0128714. doi: 10.1371/journal.pone.0128714
16. Britanova, O. V., Putintseva, E. V., Shugay, M., Merzlyak, E. M., Turchaninova, M. A., Staroverov, D. B., et al. (2014). Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689-2698. doi: 10.4049/jimmunol.1302064
17. Brown, L. E. (2010). The role of adjuvants in vaccines for seasonal and pandemic influenza. Vaccine 28, 8043-8045. doi: 10.1016/j.vaccine.2010.09.024
18. Brown, N. F., Stefanovic-Racic, M., Sipula, I. J., and Perdomo, G. (2007). The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metab. Clin. Exp. 56, 1500-1507. doi: 10.1016/j.metabol.2007.06.016
19. Bruniquel, D., and Schwartz, R. H. (2003). Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat. Immunol. 4, 235-240. doi: 10.1038/ni887
20. Brunner, S., Herndler-Brandstetter, D., Arnold, C. R., Wiegers, G. J., Villunger, A., Hackl, M., et al. (2012). Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death. Aging Cell 11, 579-587. doi: 10.1111/j.1474-9726.2012.00819.x
21. Cambier, J. (2005). Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling. Immunol. Rev. 205, 5-6. doi: 10.1111/j.0105-2896.2005.00276.x
22. Cannon, M. J. (2009). Congenital cytomegalovirus (CMV) epidemiology and awareness. J. Clin. Virol. 46(Suppl. 4), S6-S10. doi: 10.1016/j.jcv.2009.09.002
23. Cannon, M. J., Schmid, D. S., and Hyde, T. B. (2010). Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev. Med. Virol. 20, 202-213. doi: 10.1002/rmv.655
24. Carrasco, J., Godelaine, D., Pel, A. V., Boon, T., and van der Bruggen, P. (2006). CD45RA on human CD8 T cells is sensitive to the time elapsed since the last antigenic stimulation. Blood 108, 2897-2905. doi: 10.1182/blood-2005-11-007237
25. Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O'sullivan, D., et al. (2013). Posttranscriptional control of T Cell effector function by aerobic glycolysis. Cell 153, 1239-1251. doi: 10.1016/j.cell.2013.05.016
26. Chen, G., Lustig, A., and Weng, N. (2013). T cell aging: a review of the transcriptional changes determined from genome-wide analysis. Front. Immunol. 4:212. doi: 10.3389/fimmu.2013.00121
27. Chen, W. H., Kozlovsky, B. F., Effros, R. B., Grubeck-Loebenstein, B., Edelman, R., and Sztein, M. B. (2009). Vaccination in the elderly: an immunological perspective. Trends Immunol. 30, 351-359. doi: 10.1016/j.it.2009.05.002
28. Chidrawar, S., Khan, N., Wei, W., McLarnon, A., Smith, N., Nayak, L., et al. (2009). Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin. Exp. Immunol. 155, 423-432. doi: 10.1111/j.1365-2249.2008.03785.x
29. Chou, J. P., and Effros, R. B. (2013). T cell replicative senescence in human aging. Curr. Pharm. Des. 19, 1680-1698. doi: 10.2174/1381612811319090016
30. Clark, R. A. (2015). Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv1-269rv1. doi: 10.1126/scitranslmed.3010641
31. Couch, R. B., Winokur, P., Brady, R., Belshe, R., Chen, W. H., Cate, T. R., et al. (2007). Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 25, 7656-7663. doi: 10.1016/j.vaccine.2007.08.042
32. Czesnikiewicz-Guzik, M., Lee, W.-W., Cui, D., Hiruma, Y., Lamar, D. L., Yang, Z.-Z., et al. (2008). T cell subset-specific susceptibility to aging. Clin. Immunol. 127, 107-118. doi: 10.1016/j.clim.2007.12.002
33. Day, E. K., Carmichael, A. J., ten Berge, I. J. M., Waller, E. C. P., Sissons, J. G. P., and Wills, M. R. (2007). Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J. Immunol. 179, 3203-3213. doi: 10.4049/jimmunol.179.5.3203
34. Delgoffe, G. M., Kole, T. P., Zheng, Y., Zarek, P. E., Matthews, K. L., Xiao, B., et al. (2009). The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832-844. doi: 10.1016/j.immuni.2009.04.014
35. Derhovanessian, E., Maier, A. B., Beck, R., Jahn, G., Hähnel, K., Slagboom, P. E., et al. (2010). Hallmark features of immunosenescence are absent in familial longevity. J. Immunol. 185, 4618-4624. doi: 10.4049/jimmunol.1001629
36. Derhovanessian, E., Theeten, H., Hähnel, K., Van Damme, P., Cools, N., and Pawelec, G. (2013). Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine 31, 685-690. doi: 10.1016/j.vaccine.2012.11.041
37. Desai, B. N., Myers, B. R., and Schreiber, S. L. (2002). FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc. Natl. Acad. Sci. U.S.A. 99, 4319-4324. doi: 10.1073/pnas.261702698
38. Dorrington, M. G., and Bowdish, D. M. E. (2013). Immunosenescence and novel vaccination strategies for the elderly. Front. Immunol. 4:171. doi: 10.3389/fimmu.2013.00171
39. Effros, R. B. (2016). The silent war of CMV in aging and HIV infection. Mech. Ageing Dev. 158, 46-52. doi: 10.1016/j.mad.2015.09.003
40. Fann, M., Chiu, W. K., Wood, W. H., Levine, B. L., Becker, K. G., and Weng, N. (2005). Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol. Rev. 205, 190-206. doi: 10.1111/j.0105-2896.2005.00262.x
41. Farber, D. L., Yudanin, N. A., and Restifo, N. P. (2014). Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24-35. doi: 10.1038/nri3567
42. Fernández-Morera, J. L., Calvanese, V., Rodríguez-Rodero, S., Menéndez-Torre, E., and Fraga, M. F. (2010). Epigenetic regulation of the immune system in health and disease. Tissue Antigens 76, 431-439. doi: 10.1111/j.1399-0039.2010.01587.x
43. Fessler, J., Felber, A., Duftner, C., and Dejaco, C. (2013). The impact of aging on regulatory T-cells. T Cell Biol. 4:231. doi: 10.3389/fimmu.2013.00231
44. Flavell, R. A., Herndler-Brandstetter, D., and Ishigame, H. (2013). How to define biomarkers of human T cell aging and immunocompetence? Front. Immunol. 4:136. doi: 10.3389/fimmu.2013.00136
45. Fowler, K. B., Stagno, S., Pass, R. F., Britt, W. J., Boll, T. J., and Alford, C. A. (1992). The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N. Engl. J. Med. 326, 663-667. doi: 10.1056/NEJM199203053261003
46. Franceschi, C., Bonafè, M., and Valensin, S. (2000). Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18, 1717-1720. doi: 10.1016/S0264-410X(99)00513-7
47. Frebel, H., Richter, K., and Oxenius, A. (2010). How chronic viral infections impact on antigen-specific T-cell responses. Eur. J. Immunol. 40, 654-663. doi: 10.1002/eji.200940102
48. Freund, A., Orjalo, A. V., Desprez, P.-Y., and Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238-246. doi: 10.1016/j.molmed.2010.03.003
49. Fuente, M. D. (2014). "The immune system, a marker and modulator of the rate of aging, "in Immunology of Aging, eds A. Massoud and N. Rezaei (Berlin; Heidelberg: Springer), 3-23.
50. Gamadia, L. E., Remmerswaal, E. B. M., Weel, J. F., Bemelman, F., van Lier, R. A. W., and Ten Berge, I. J. M. (2003). Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 101, 2686-2692. doi: 10.1182/blood-2002-08-2502
51. Gamadia, L. E., Rentenaar, R. J., Baars, P. A., Remmerswaal, E. B., Surachno, S., Weel, J. F., et al. (2001). Differentiation of cytomegalovirus-specific CD8(+) T cells in healthy and immunosuppressed virus carriers. Blood 98, 754-761. doi: 10.1182/blood. V98.3.754
52. Garg, S. K., Delaney, C., Toubai, T., Ghosh, A., Reddy, P., Banerjee, R., et al. (2014). Aging is associated with increased regulatory T-cell function. Aging Cell 13, 441-448. doi: 10.1111/acel.12191
53. Genini, E., Percivalle, E., Sarasini, A., Revello, M. G., Baldanti, F., and Gerna, G. (2011). Serum antibody response to the gH/gL/pUL128-131 five-protein complex of human cytomegalovirus (HCMV) in primary and reactivated HCMV infections. J. Clin. Virol. 52, 113-118. doi: 10.1016/j.jcv.2011.06.018
54. Gerna, G., Sarasini, A., Patrone, M., Percivalle, E., Fiorina, L., Campanini, G., et al. (2008). Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. J. Gen. Virol. 89, 853-865. doi: 10.1099/vir.0.83523-0
55. Gibney, E. R., and Nolan, C. M. (2010). Epigenetics and gene expression. Heredity 105, 4-13. doi: 10.1038/hdy.2010.54
56. Gibson, W. (2008). Structure and formation of the cytomegalovirus virion. Curr. Top. Microbiol. Immunol. 325, 187-204. doi: 10.1007/978-3-540-77349-8_11
57. Goodrum, F. D., Jordan, C. T., High, K., and Shenk, T. (2002). Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc. Natl. Acad. Sci. U.S.A. 99, 16255-16260. doi: 10.1073/pnas.252630899
58. Goronzy, J. J., Fang, F., Cavanagh, M. M., Qi, Q., and Weyand, C. M. (2015). Naive T cell maintenance and function in human aging. J. Immunol. 194, 4073-4080. doi: 10.4049/jimmunol.1500046
59. Grolleau-Julius, A., Ray, D., and Yung, R. L. (2009). The role of epigenetics in aging and autoimmunity. Clin. Rev. Allergy Immunol. 39, 42-50. doi: 10.1007/s12016-009-8169-3
60. Gubser, P. M., Bantug, G. R., Razik, L., Fischer, M., Dimeloe, S., Hoenger, G., et al. (2013). Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064-1072. doi: 10.1038/ni.2687
61. Hahn, G., Jores, R., and Mocarski, E. S. (1998). Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc. Natl. Acad. Sci. U. S. A. 95, 3937-3942.
62. Hammarlund, E., Lewis, M. W., Carter, S. V., Amanna, I., Hansen, S. G., Strelow, L. I., et al. (2005). Multiple diagnostic techniques identify previously vaccinated individuals with protective immunity against monkeypox. Nat. Med. 11, 1005-1011. doi: 10.1038/nm1273
63. Hammarlund, E., Lewis, M. W., Hansen, S. G., Strelow, L. I., Nelson, J. A., Sexton, G. J., et al. (2003). Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9, 1131-1137. doi: 10.1038/nm917
64. Hanley, P. J., and Bollard, C. M. (2014). Controlling cytomegalovirus: helping the immune system take the lead. Viruses 6, 2242-2258. doi: 10.3390/v6062242
65. Hassouneh, F., Campos, C., López-Sejas, N., Alonso, C., Tarazona, R., Solana, R., et al. (2016). Effect of age and latent CMV infection on CD8+ CD56+ T cells (NKT-like) frequency and functionality. Mech. Ageing Dev. 158, 38-45. doi: 10.1016/j.mad.2015.12.003
66. Haussig, J. M., Burgold, J., Hafalla, J. C. R., Matuschewski, K., and Kooij, T. W. A. (2014). Signatures of malaria vaccine efficacy in ageing murine immune memory. Parasite Immunol. 36, 199-206. doi: 10.1111/pim.12104
67. Haynes, L., Eaton, S. M., Burns, E. M., Randall, T. D., and Swain, S. L. (2003). 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, 15053-15058. doi: 10.1073/pnas.2433717100
68. Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., et al. (2014). p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004-4016. doi: 10.1172/JCI75051
69. Herndler-Brandstetter, D., Landgraf, K., Tzankov, A., Jenewein, B., Brunauer, R., Laschober, G. T., et al. (2012). The impact of aging on memory T cell phenotype and function in the human bone marrow. J. Leukoc. Biol. 91, 197-205. doi: 10.1189/jlb.0611299
70. Hewagama, A., and Richardson, B. (2009). The genetics and epigenetics of autoimmune diseases. J. Autoimmun. 33, 3-11. doi: 10.1016/j.jaut.2009.03.007
71. Heyn, H., Li, N., Ferreira, H. J., Moran, S., Pisano, D. G., Gomez, A., et al. (2012). Distinct DNA methylomes of newborns and centenarians. Proc. Natl. Acad. Sci. U.S.A. 109, 10522-10527. doi: 10.1073/pnas.1120658109
72. Hongdong, L., Guini, H., and Zheng, G. (2015). [Age-related DNA methylation changes in peripheral whole blood]. Yi Chuan 37, 165-173. doi: 10.16288/j.yczz.14-394
73. Huang, M.-C., Liao, J.-J., Bonasera, S., Longo, D. L., and Goetzl, E. J. (2008). Nuclear factor-κB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J. 22, 2142-2150. doi: 10.1096/fj.07-103721
74. Invernizzi, P. (2009). Future directions in genetic for autoimmune diseases. J. Autoimmun. 33, 1-2. doi: 10.1016/j.jaut.2009.03.001
75. Jackson, S. E., Mason, G. M., and Wills, M. R. (2011). Human cytomegalovirus immunity and immune evasion. Virus Res. 157, 151-160. doi: 10.1016/j.virusres.2010.10.031
76. Jacomet, F., Cayssials, E., Basbous, S., Levescot, A., Piccirilli, N., Desmier, D., et al. (2015). Evidence for eomesodermin-expressing innate-like CD8+ KIR/NKG2A+ T cells in human adults and cord blood samples. Eur. J. Immunol. 45, 1926-1933. doi: 10.1002/eji.201545539
77. Jefferson, T., Rivetti, D., Rivetti, A., Rudin, M., Di Pietrantonj, C., and Demicheli, V. (2005). Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet Lond. Engl. 366, 1165-1174. doi: 10.1016/S0140-6736(05)67339-4
78. Jones, R. G., and Thompson, C. B. (2007). Revving the engine: signal transduction fuels T cell activation. Immunity 27, 173-178. doi: 10.1016/j.immuni.2007.07.008
79. Joshi, N. S., Cui, W., Dominguez, C. X., Chen, J. H., Hand, T. W., and Kaech, S. M. (2011). Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J. Immunol. 187, 4068-4076. doi: 10.4049/jimmunol.1002145
80. Karrer, U., Sierro, S., Wagner, M., Oxenius, A., Hengel, H., Koszinowski, U. H., et al. (2003). Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J. Immunol. 170, 2022-2029. doi: 10.4049/jimmunol.170.4.2022
81. Kawakami, K., Nakamura, A., Ishigami, A., Goto, S., and Takahashi, R. (2008). Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10, 415-421. doi: 10.1007/s10522-008-9176-0
82. Khan, N., Hislop, A., Gudgeon, N., Cobbold, M., Khanna, R., Nayak, L., et al. (2004). Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J. Immunol. 173, 7481-7489. doi: 10.4049/jimmunol.173.12.7481
83. Khan, N., Shariff, N., Cobbold, M., Bruton, R., Ainsworth, J. A., Sinclair, A. J., et al. (2002). Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169, 1984-1992. doi: 10.4049/jimmunol.169.4.1984
84. Khurana, S., Verma, N., Yewdell, J. W., Hilbert, A. K., Castellino, F., Lattanzi, M., et al. (2011). MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci. Transl. Med. 3, 85ra48. doi: 10.1126/scitranslmed.3002336
85. Klenerman, P., and Oxenius, A. (2016). T cell responses to cytomegalovirus. Nat. Rev. Immunol. 16, 367-377. doi: 10.1038/nri.2016.38
86. Koch, S., Larbi, A., Derhovanessian, E., özcelik, D., Naumova, E., and Pawelec, G. (2008). Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing 5:6. doi: 10.1186/1742-4933-5-6
87. Koch, S., Larbi, A., Ozcelik, D., Solana, R., Gouttefangeas, C., Attig, S., et al. (2007). Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann. N. Y. Acad. Sci. 1114, 23-35. doi: 10.1196/annals.1396.043
88. Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705. doi: 10.1016/j.cell.2007.02.005
89. Kuijpers, T. W., Vossen, M. T., Gent, M.-R., Davin, J.-C., Roos, M. T., Wertheim-van Dillen, P. M., et al. (2003). Frequencies of circulating cytolytic, CD45RA+CD27-, CD8+ T lymphocytes depend on infection with CMV. J. Immunol. 170, 4342-4348. doi: 10.4049/jimmunol.170.8.4342
90. Kundu, S., and Peterson, C. L. (2009). Role of chromatin states in transcriptional memory. Biochim. Biophys. Acta (BBA)-Gen. Subj. 1790, 445-455. doi: 10.1016/j.bbagen.2009.02.009
91. Lazarevic, V., Glimcher, L. H., and Lord, G. M. (2013). T-bet: a bridge between innate and adaptive immunity. Nat. Rev. Immunol. 13, 777-789. doi: 10.1038/nri3536
92. Lazuardi, L., Jenewein, B., Wolf, A. M., Pfister, G., Tzankov, A., and Grubeck-Loebenstein, B. (2005). Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology 114, 37-43. doi: 10.1111/j.1365-2567.2004.02006.x
93. Lee, J. S., Lee, W.-W., Kim, S. H., Kang, Y., Lee, N., Shin, M. S., et al. (2011). Age-associated alteration in naive and memory Th17 cell response in humans. Clin. Immunol. 140, 84-91. doi: 10.1016/j.clim.2011.03.018
94. Lesourd, B. M., Mazari, L., and Ferry, M. (1998). The role of nutrition in immunity in the aged. Nutr. Rev. 56, S113-S125.
95. Li, G., Yu, M., Lee, W.-W., Tsang, M., Krishnan, E., Weyand, C. M., et al. (2012). Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518-1524. doi: 10.1038/nm.2963
96. Li, H., Margolick, J. B., Bream, J. H., Nilles, T. L., Langan, S., Bui, H. T., et al. (2014). Heterogeneity of CD4+ and CD8+ T-cell responses to cytomegalovirus in HIV-infected and HIV-uninfected men who have sex with men. J. Infect. Dis. 210, 400-404. doi: 10.1093/infdis/jiu093
97. Li, Q.-J., Chau, J., Ebert, P. J. R., Sylvester, G., Min, H., Liu, G., et al. (2007). miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147-161. doi: 10.1016/j.cell.2007.03.008
98. Lim, M.-A., Lee, J., Park, J.-S., Jhun, J.-Y., Moon, Y.-M., Cho, M.-L., et al. (2014). Increased Th17 differentiation in aged mice is significantly associated with high IL-1β level and low IL-2 expression. Exp. Gerontol. 49, 55-62. doi: 10.1016/j.exger.2013.10.006
99. Ludwig, A., and Hengel, H. (2009). Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. Euro Surveill. 14, 26-32.
100. Macagno, A., Bernasconi, N. L., Vanzetta, F., Dander, E., Sarasini, A., Revello, M. G., et al. (2010). Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J. Virol. 84, 1005-1013. doi: 10.1128/JVI.01809-09
101. Mackus, W. J. M., Frakking, F. N. J., Grummels, A., Gamadia, L. E., De Bree, G. J., Hamann, D., et al. (2003). Expansion of CMV-specific CD8+CD45RA+CD27-T cells in B-cell chronic lymphocytic leukemia. Blood 102, 1057-1063. doi: 10.1182/blood-2003-01-0182
102. Mahnke, Y. D., Brodie, T. M., Sallusto, F., Roederer, M., and Lugli, E. (2013). The who's who of T-cell differentiation: human memory T-cell subsets. Eur. J. Immunol. 43, 2797-2809. doi: 10.1002/eji.201343751
103. Maijó, M., Clements, S. J., Ivory, K., Nicoletti, C., and Carding, S. R. (2014). Nutrition, diet and immunosenescence. Mech. Ageing Dev. 136-137, 116-128. doi: 10.1016/j.mad.2013.12.003
104. Mannick, J. B., Giudice, G. D., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., et al. (2014). mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179-268ra179. doi: 10.1126/scitranslmed.3009892
105. Mekker, A., Tchang, V. S., Haeberli, L., Oxenius, A., Trkola, A., and Karrer, U. (2012). Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 8:e1002850. doi: 10.1371/journal.ppat.1002850
106. Miller, J. D., van der Most, R. G., Akondy, R. S., Glidewell, J. T., Albott, S., Masopust, D., et al. (2008). Human effector and memory CD8+ T Cell responses to smallpox and yellow fever vaccines. Immunity 28, 710-722. doi: 10.1016/j.immuni.2008.02.020
107. Miller, R. A. (1996). The aging immune system: primer and prospectus. Science 273, 70-74.
108. Miller, R. A., Buehner, G., Chang, Y., Harper, J. M., Sigler, R., and Smith-Wheelock, M. (2005). Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119-125. doi: 10.1111/j.1474-9726.2005.00152.x
109. Moro-García, M. A., Alonso-Arias, R., and López-Larrea, C. (2013). When Aging Reaches CD4+ T-cells: phenotypic and functional changes. Front. Immunol. 4:107. doi: 10.3389/fimmu.2013.00107
110. Mueller, S. N., Gebhardt, T., Carbone, F. R., and Heath, W. R. (2013). Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137-161. doi: 10.1146/annurev-immunol-032712-095954
111. Muthusamy, N., Barton, K., and Leiden, J. M. (1995). Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377, 639-642. doi: 10.1038/377639a0
112. Naylor, K., Li, G., Vallejo, A. N., Lee, W.-W., Koetz, K., Bryl, E., et al. (2005). The influence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446-7452. doi: 10.4049/jimmunol.174.11.7446
113. Nikolich-Žugich, J. (2008). Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8, 512-522. doi: 10.1038/nri2318
114. Nikolich-Žugich, J. (2014). Aging of the T cell compartment in mice and humans: from no naïve expectations to foggy memories. J. Immunol. 193, 2622-2629. doi: 10.4049/jimmunol.1401174
115. Nikolich-Žugich, J., and Rudd, B. D. (2010). Immune memory and aging: an infinite or finite resource? Curr. Opin. Immunol. 22, 535-540. doi: 10.1016/j.coi.2010.06.011
116. Noriega, V., Redmann, V., Gardner, T., and Tortorella, D. (2012). Diverse immune evasion strategies by human cytomegalovirus. Immunol. Res. 54, 140-151. doi: 10.1007/s12026-012-8304-8
117. O'Hara, G. A., Welten, S. P. M., Klenerman, P., and Arens, R. (2012). Memory T cell inflation: understanding cause and effect. Trends Immunol. 33, 84-90. doi: 10.1016/j.it.2011.11.005
118. Ohyashiki, M., Ohyashiki, J. H., Hirota, A., Kobayashi, C., and Ohyashiki, K. (2011). Age-related decrease of miRNA-92a levels in human CD8+ T-cells correlates with a reduction of naïve T lymphocytes. Immun. Ageing 8:11. doi: 10.1186/1742-4933-8-11
119. Pae, M., Meydani, S. N., and Wu, D. (2011). The Role of nutrition in enhancing immunity in aging. Aging Dis. 3, 91-129.
120. Papagno, L., Spina, C. A., Marchant, A., Salio, M., Rufer, N., Little, S., et al. (2004). Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2:E20. doi: 10.1371/journal.pbio.0020020
121. Paulus, C., and Nevels, M. (2009). The human cytomegalovirus major immediate-early proteins as antagonists of intrinsic and innate antiviral host responses. Viruses 1, 760-779. doi: 10.3390/v1030760
122. Pawelec, G. (2005). Immunosenescence and vaccination. Immun. Ageing 2:16. doi: 10.1186/1742-4933-2-16
123. Pawelec, G., Akbar, A., Caruso, C., Solana, R., Grubeck-Loebenstein, B., and Wikby, A. (2005). Human immunosenescence: is it infectious? Immunol. Rev. 205, 257-268. doi: 10.1111/j.0105-2896.2005.00271.x
124. Pawelec, G., Derhovanessian, E., Larbi, A., Strindhall, J., and Wikby, A. (2009). Cytomegalovirus and human immunosenescence. Rev. Med. Virol. 19, 47-56. doi: 10.1002/rmv.598
125. Peng, T., Golub, T. R., and Sabatini, D. M. (2002). The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell. Biol. 22, 5575-5584. doi: 10.1128/MCB.22.15.5575-5584.2002
126. Pera, A., Campos, C., Corona, A., Sanchez-Correa, B., Tarazona, R., Larbi, A., et al. (2014). CMV Latent Infection Improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PLoS ONE 9:e88538. doi: 10.1371/journal.pone.0088538
127. Polic, B., Hengel, H., Krmpotic, A., Trgovcich, J., Pavic, I., Luccaronin, P., et al. (1998). Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J. Exp. Med. 188, 1047-1054.
128. Ponnappan, S., and Ponnappan, U. (2011). Aging and immune function: molecular mechanisms to interventions. Antioxid. Redox Signal. 14, 1551-1585. doi: 10.1089/ars.2010.3228
129. Pourgheysari, B., Khan, N., Best, D., Bruton, R., Nayak, L., and Moss, P. A. H. (2007). The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J. Virol. 81, 7759-7765. doi: 10.1128/JVI.01262-06
130. Precopio, M. L., Betts, M. R., Parrino, J., Price, D. A., Gostick, E., Ambrozak, D. R., et al. (2007). Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 204, 1405-1416. doi: 10.1084/jem.20062363
131. Ramanathan, A., and Schreiber, S. L. (2009). Direct control of mitochondrial function by mTOR. Proc. Natl. Acad. Sci. U.S.A. 106, 22229-22232. doi: 10.1073/pnas.0912074106
132. Rao, R. R., Li, Q., Odunsi, K., and Shrikant, P. A. (2010). The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 32, 67-78. doi: 10.1016/j.immuni.2009.10.010
133. Reeves, M. B., MacAry, P. A., Lehner, P. J., Sissons, J. G. P., and Sinclair, J. H. (2005). Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc. Natl. Acad. Sci. U.S.A. 102, 4140-4145. doi: 10.1073/pnas.0408994102
134. Reeves, M., and Sinclair, J. (2008). Aspects of human cytomegalovirus latency and reactivation. Curr. Top. Microbiol. Immunol. 325, 297-313. doi: 10.1007/978-3-540-77349-8_17
135. Renkema, K. R., Li, G., Wu, A., Smithey, M. J., and Nikolich-Žugich, J. (2014). Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J. Immunol. 192, 151-159. doi: 10.4049/jimmunol.1301453
136. Rentenaar, R. J., Gamadia, L. E., van DerHoek, N., van Diepen, F. N., Boom, R., Weel, J. F., et al. (2000). Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection. J. Clin. Invest. 105, 541-548. doi: 10.1172/JCI8229
137. Revello, M. G., and Gerna, G. (2002). Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin. Microbiol. Rev. 15, 680-715. doi: 10.1128/CMR.15.4.680-715.2002
138. Ron-Harel, N., Sharpe, A. H., and Haigis, M. C. (2015). Mitochondrial metabolism in T cell activation and senescence: a mini-review. Gerontology 61, 131-138. doi: 10.1159/000362502
139. Sallusto, F., Lenig, D., Förster, R., Lipp, M., and Lanzavecchia, A. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708-712. doi: 10.1038/44385
140. Salpea, P., Russanova, V. R., Hirai, T. H., Sourlingas, T. G., Sekeri-Pataryas, K. E., Romero, R., et al. (2012). Postnatal development-and age-related changes in DNA-methylation patterns in the human genome. Nucleic Acids Res. 40, 6477-6494. doi: 10.1093/nar/gks312
141. Sansoni, P., Vescovini, R., Fagnoni, F., Biasini, C., Zanni, F., Zanlari, L., et al. (2008). The immune system in extreme longevity. Exp. Gerontol. 43, 61-65. doi: 10.1016/j.exger.2007.06.008
142. Sansoni, P., Vescovini, R., Fagnoni, F. F., Akbar, A., Arens, R., Chiu, Y.-L., et al. (2014). New advances in CMV and immunosenescence. Exp. Gerontol. 55, 54-62. doi: 10.1016/j.exger.2014.03.020
143. Sathaliyawala, T., Kubota, M., Yudanin, N., Turner, D., Camp, P., Thome, J. J. C., et al. (2013). Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187-197. doi: 10.1016/j.immuni.2012.09.020
144. Saurwein-Teissl, M., Lung, T. L., Marx, F., Gschösser, C., Asch, E., Blasko, I., et al. (2002). 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, 5893-5899. doi: 10.4049/jimmunol.168.11.5893
145. Schleiss, M. R. (2013). Cytomegalovirus in the neonate: immune correlates of infection and protection. Clin. Dev. Immunol. 2013:501801. doi: 10.1155/2013/501801. Available online at: https://www.hindawi.com/journals/jir/2013/501801/cta/
146. Shanley, D. P., Aw, D., Manley, N. R., and Palmer, D. B. (2009). An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol. 30, 374-381. doi: 10.1016/j.it.2009.05.001
147. Sidler, C., Woycicki, R., Ilnytskyy, Y., Metz, G., Kovalchuk, I., and Kovalchuk, O. (2013). Immunosenescence is associated with altered gene expression and epigenetic regulation in primary and secondary immune organs. Genet. Aging 4:211. doi: 10.3389/fgene.2013.00211
148. Sinclair, J., and Sissons, P. (2006). Latency and reactivation of human cytomegalovirus. J. Gen. Virol. 87, 1763-1779. doi: 10.1099/vir.0.81891-0
149. Sipula, I. J., Brown, N. F., and Perdomo, G. (2006). Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metab. Clin. Exp. 55, 1637-1644. doi: 10.1016/j.metabol.2006.08.002
150. Snyder, L. D., Chan, C., Kwon, D., Yi, J. S., Martissa, J. A., Finlen Copeland, C. A., et al. (2016). Polyfunctional T-cell signatures predict protection from cytomegalovirus after lung transplant. Am. J. Respir. Crit. Care Med. 193, 78-85. doi: 10.1164/rccm.201504-0733OC
151. Solana, R., Tarazona, R., Aiello, A. E., Akbar, A. N., Appay, V., Beswick, M., et al. (2012a). CMV and Immunosenescence: from basics to clinics. Immun. Ageing 9:23. doi: 10.1186/1742-4933-9-23
152. Solana, R., Tarazona, R., Gayoso, I., Lesur, O., Dupuis, G., and Fulop, T. (2012b). Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin. Immunol. 24, 331-341. doi: 10.1016/j.smim.2012.04.008
153. Sprent, J., and Surh, C. D. (2011). Normal T cell homeostasis: the conversion of naïve cells into memory-phenotype cells. Nat. Immunol. 12, 478-484. doi: 10.1038/ni.2018
154. Strahl, B. D., and Allis, C. D. (2000). The language of covalent histone modifications. Nature 403, 41-45. doi: 10.1038/47412
155. Sylwester, A. W., Mitchell, B. L., Edgar, J. B., Taormina, C., Pelte, C., Ruchti, F., et al. (2005). Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673-685. doi: 10.1084/jem.20050882
156. Tesar, B. M., Du, W., Shirali, A., Walker, W. E., Shen, H., and Goldstein, D. R. (2009). Aging augments IL-17 T cell alloimmune responses. Am. J. Transplant. 9, 54-63. doi: 10.1111/j.1600-6143.2008.02458.x
157. Tserel, L., Kolde, R., Limbach, M., Tretyakov, K., Kasela, S., Kisand, K., et al. (2015). Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci. Rep. 5:13107. doi: 10.1038/srep13107. Available online at: http://www.nature.com/articles/srep13107
158. Turner, B. M. (2003). Memorable transcription. Nat. Cell Biol. 5, 390-393. doi: 10.1038/ncb0503-390
159. Valkenburg, S. A., Venturi, V., Dang, T. H. Y., Bird, N. L., Doherty, P. C., Turner, S. J., et al. (2012). Early priming minimizes the age-related immune compromise of CD8+ T cell diversity and function. PLoS Pathog. 8:e1002544. doi: 10.1371/journal.ppat.1002544
160. Van Epps, P., Banks, R., Aung, H., Betts, M. R., and Canaday, D. H. (2014). Age-related differences in polyfunctional T cell responses. Immun. Ageing 11:14. doi: 10.1186/1742-4933-11-14
161. van Leeuwen, E. M. M., Remmerswaal, E. B. M., Heemskerk, M. H. M., ten Berge, I. J. M., and van Lier, R. A. W. (2006). Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. Blood 108, 3121-3127. doi: 10.1182/blood-2006-03-006809
162. Vieira Braga, F. A., Hertoghs, K. M. L., van Lier, R. A. W., and van Gisbergen, K. P. J. M. (2015). Molecular characterization of HCMV-specific immune responses: parallels between CD8(+) T cells, CD4(+) T cells, and NK cells. Eur. J. Immunol. 45, 2433-2445. doi: 10.1002/eji.201545495
163. Wang, D., and Shenk, T. (2005). Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc. Natl. Acad. Sci. U.S.A. 102, 18153-18158. doi: 10.1073/pnas.0509201102
164. Weinberger, B., Herndler-Brandstetter, D., Schwanninger, A., Weiskopf, D., and Grubeck-Loebenstein, B. (2008). Biology of immune responses to vaccines in elderly persons. Clin. Infect. Dis. 46, 1078-1084. doi: 10.1086/529197
165. Wells, A. D. (2009). New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J. Immunol. 182, 7331-7341. doi: 10.4049/jimmunol.0803917
166. Weltevrede, M., Eilers, R., de Melker, H. E., and van Baarle, D. (2016). Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review. Exp. Gerontol. 77, 87-95. doi: 10.1016/j.exger.2016.02.005
167. Wertheimer, A. M., Bennett, M. S., Park, B., Uhrlaub, J. L., Martinez, C., Pulko, V., et al. (2014). Aging and cytomegalovirus (CMV) infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143-2155. doi: 10.4049/jimmunol.1301721
168. Wherry, E. J. (2011). T cell exhaustion. Nat. Immunol. 12, 492-499. doi: 10.1038/ni.2035
169. Wherry, E. J., and Kurachi, M. (2015). Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486-499. doi: 10.1038/nri3862
170. Wikby, A., Ferguson, F., Forsey, R., Thompson, J., Strindhall, J., Löfgren, S., et al. (2005). An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J. Gerontol. A. Biol. Sci. Med. Sci. 60, 556-565. doi: 10.1093/gerona/60.5.556
171. Wikby, A., Månsson, I. A., Johansson, B., Strindhall, J., and Nilsson, S. E. (2008). The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age. Biogerontology 9, 299-308. doi: 10.1007/s10522-008-9138-6
172. Winkler, T. H., and Waisman, A. (2014). With a little help from my old T cell: memory follicular T helper cells driving autoimmunity? Eur. J. Immunol. 44, 2869-2871. doi: 10.1002/eji.201445101
173. Yamamoto, T., Iwamoto, N., Yamamoto, H., Tsukamoto, T., Kuwano, T., Takeda, A., et al. (2009). Polyfunctional CD4+ T-Cell induction in neutralizing antibody-triggered control of simian immunodeficiency virus infection. J. Virol. 83, 5514-5524. doi: 10.1128/JVI.00145-09
174. Yano, S., Ghosh, P., Kusaba, H., Buchholz, M., and Longo, D. L. (2003). Effect of promoter methylation on the regulation of IFN-γ gene during in vitro differentiation of human peripheral blood T cells into a Th2 population. J. Immunol. 171, 2510-2516. doi: 10.4049/jimmunol.171.5.2510
175. Zediak, V. P., Wherry, E. J., and Berger, S. L. (2011). The contribution of epigenetic memory to immunologic memory. Curr. Opin. Genet. Dev. 21, 154-159. doi: 10.1016/j.gde.2011.01.016
176. Zhang, W., Brahmakshatriya, V., and Swain, S. L. (2014). CD4 T cell defects in the aged: causes, consequences and strategies to circumvent. Exp. Gerontol. 0, 67-70. doi: 10.1016/j.exger.2014.01.002
177. Zhou, M., Zou, R., Gan, H., Liang, Z., Li, F., Lin, T., et al. (2014). The effect of aging on the frequency, phenotype and cytokine production of human blood CD4 + CXCR5 + T follicular helper cells: comparison of aged and young subjects. Immun. Ageing 11:12. doi: 10.1186/1742-4933-11-12