Lymphocyte Subtypes and Functions in Centenarians as Models for Successful Aging

  • Elena Bianchini
  • Simone Pecorini
  • Sara De Biasi
  • Lara Gibellini
  • Milena Nasi
  • Andrea CossarizzaEmail author
  • Marcello Pinti
Living reference work entry


Several cell subsets participate to the immune response, and their close interplay is fundamental for the successful elimination of harmful pathogens. Immune system undergoes a progressive and profound remodeling of its functions with aging. This process is evidenced by a continuous change in the relative percentages, absolute number, and functionality of the subsets of lymphocytes that ultimately form the immune system.

In this chapter, we describe the main changes in lymphocyte subtypes and functions that occur with age, paying particular attention to centenarians, exceptional individuals who reach the extreme limits of human life in good state of health. A particular emphasis is dedicated to changes observed in particular subsets, like regulatory T cells, invariant natural killer T cells, or mucosal-associated invariant T cells, whose role in many chronic inflammatory diseases or autoimmune diseases has been recently evidenced.


Centenarians Polychromatic flow cytometry Successful aging Treg 



Sara De Biasi is an International Society for Advancement of Cytometry (ISAC) Marylou Ingram Scholar.


  1. Aberle JH, Stiasny K, Kundi M, Heinz FX (2013) Mechanistic insights into the impairment of memory B cells and antibody production in the elderly. Age (Dordr) 35:371–381CrossRefGoogle Scholar
  2. Agematsu K, Nagumo H, Yang FC, Nakazawa T, Fukushima K, Ito S et al (1997) B cell subpopulations separated by CD27 and crucial collaboration of CD27+ B cells and helper T cells in immunoglobulin production. Eur J Immunol 27:2073–2079PubMedCrossRefGoogle Scholar
  3. Agematsu K, Hokibara S, Nagumo H, Komiyama A (2000) CD27: a memory B-cell marker. Immunol Today 21:204–206PubMedCrossRefGoogle Scholar
  4. Akbar AN, Fletcher JM (2005) Memory T cell homeostasis and senescence during aging. Curr Opin Immunol 17:480–485PubMedCrossRefGoogle Scholar
  5. Al-Attar A, Presnell SR, Peterson CA, Thomas DT, Lutz CT (2016) The effect of sex on immune cells in healthy aging: elderly women have more robust natural killer lymphocytes than do elderly men. Mech Ageing Dev 156:25–33PubMedCrossRefGoogle Scholar
  6. Argentati K, Re F, Donnini A, Tucci MG, Franceschi C, Bartozzi B et al (2002) Numerical and functional alterations of circulating gammadelta T lymphocytes in aged people and centenarians. J Leukoc Biol 72:65–71PubMedGoogle Scholar
  7. Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B (2011) Gain and loss of T cell subsets in old age –age-related reshaping of the T cell repertoire. J Clin Immunol 31:137–146PubMedCrossRefGoogle Scholar
  8. Bagnara GP, Bonsi L, Strippoli P, Bonifazi F, Tonelli R, D’Addato S et al (2000) Hemopoiesis in healthy old people and centenarians: well-maintained responsiveness of CD34+ cells to hemopoietic growth factors and remodeling of cytokine network. J Gerontol A Biol Sci Med Sci 55:B61–B66. discussion B67–70PubMedCrossRefGoogle Scholar
  9. Berzins SP, Smyth MJ, Baxter AG (2011) Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 11:131–142PubMedCrossRefGoogle Scholar
  10. Bianchini E, De Biasi S, Simone AM, Ferraro D, Sola P, Cossarizza A et al (2017) Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis. Immunol Lett 183:1–7PubMedCrossRefGoogle Scholar
  11. Bjorkstrom NK, Ljunggren HG, Sandberg JK (2010) CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 31:401–406PubMedCrossRefGoogle Scholar
  12. Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B et al (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34:253–265PubMedCrossRefGoogle Scholar
  13. Britanova OV, Shugay M, Merzlyak EM, Staroverov DB, Putintseva EV, Turchaninova MA et al (2016) Dynamics of individual T cell repertoires: from cord blood to centenarians. J Immunol 196:5005–5013PubMedCrossRefGoogle Scholar
  14. Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (2001) Decreased natural killer cell activity is associated with atherosclerosis in elderly humans. Exp Gerontol 37:127–136PubMedCrossRefGoogle Scholar
  15. Buffa S, Bulati M, Pellicano M, Dunn-Walters DK, Wu YC, Candore G et al (2011) B cell immunosenescence: different features of naive and memory B cells in elderly. Biogerontology 12:473–483PubMedCrossRefGoogle Scholar
  16. Buffa S, Pellicano M, Bulati M, Martorana A, Goldeck D, Caruso C et al (2013) A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(−)CD24 (−) B cells in centenarian offspring and elderly people. Age (Dordr) 35:2009–2024CrossRefGoogle Scholar
  17. Caccamo N, Dieli F, Wesch D, Jomaa H, Eberl M (2006) Sex-specific phenotypical and functional differences in peripheral human Vgamma9/Vdelta2 T cells. J Leukoc Biol 79:663–666PubMedCrossRefGoogle Scholar
  18. Chen ZW, Letvin NL (2003) Vgamma2Vdelta2+ T cells and anti-microbial immune responses. Microbes Infect 5:491–498PubMedPubMedCentralCrossRefGoogle Scholar
  19. Clambey ET, van Dyk LF, Kappler JW, Marrack P (2005) Non-malignant clonal expansions of CD8+ memory T cells in aged individuals. Immunol Rev 205:170–189PubMedCrossRefGoogle Scholar
  20. Colonna-Romano G, Aquino A, Bulati M, Lio D, Candore G, Oddo G et al (2004) Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence. Exp Gerontol 39:1439–1446PubMedCrossRefGoogle Scholar
  21. Colonna-Romano G, Aquino A, Bulati M, Di Lorenzo G, Listi F, Vitello S et al (2006) Memory B cell subpopulations in the aged. Rejuvenation Res 9:149–152PubMedCrossRefGoogle Scholar
  22. Colonna-Romano G, Bulati M, Aquino A, Pellicano M, Vitello S, Lio D et al (2009) A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev 130:681–690PubMedCrossRefGoogle Scholar
  23. Cossarizza A, Frasca D (2014) Aging and longevity: an immunological perspective. Immunol Lett 162:279–280PubMedCrossRefGoogle Scholar
  24. Cossarizza A, Monti D, Bersani F, Paganelli R, Montagnani G, Cadossi R et al (1989) Extremely low frequency pulsed electromagnetic fields increase interleukin-2 (IL-2) utilization and IL-2 receptor expression in mitogen-stimulated human lymphocytes from old subjects. FEBS Lett 248:141–144PubMedCrossRefGoogle Scholar
  25. Cossarizza A, Ortolani C, Paganelli R, Barbieri D, Monti D, Sansoni P et al (1996) CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory. Mech Ageing Dev 86:173–195PubMedCrossRefGoogle Scholar
  26. Cossarizza A, Ortolani C, Monti D, Franceschi C (1997) Cytometric analysis of immunosenescence. Cytometry 27:297–313PubMedCrossRefGoogle Scholar
  27. Crough T, Purdie DM, Okai M, Maksoud A, Nieda M, Nicol AJ (2004) Modulation of human Valpha24(+)Vbeta11(+) NKT cells by age, malignancy and conventional anticancer therapies. Br J Cancer 91:1880–1886PubMedPubMedCentralCrossRefGoogle Scholar
  28. D’Andrea A, Goux D, De Lalla C, Koezuka Y, Montagna D, Moretta A et al (2000) Neonatal invariant Valpha24+ NKT lymphocytes are activated memory cells. Eur J Immunol 30:1544–1550PubMedCrossRefGoogle Scholar
  29. De Biasi S, Simone AM, Nasi M, Bianchini E, Ferraro D, Vitetta F et al (2016) iNKT cells in secondary progressive multiple sclerosis patients display pro-inflammatory profiles. Front Immunol 7:555PubMedPubMedCentralCrossRefGoogle Scholar
  30. De Rosa SC, Andrus JP, Perfetto SP, Mantovani JJ, Herzenberg LA, Roederer M (2004) Ontogeny of gamma delta T cells in humans. J Immunol 172:1637–1645PubMedCrossRefGoogle Scholar
  31. Dejaco C, Duftner C, Schirmer M (2006) Are regulatory T-cells linked with aging? Exp Gerontol 41:339–345PubMedCrossRefGoogle Scholar
  32. DelaRosa O, Tarazona R, Casado JG, Alonso C, Ostos B, Pena J et al (2002) Valpha24+ NKT cells are decreased in elderly humans. Exp Gerontol 37:213–217PubMedCrossRefGoogle Scholar
  33. Derhovanessian E, Maier AB, Hahnel K, Zelba H, de Craen AJ, Roelofs H et al (2013) Lower proportion of naive peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. Age (Dordr) 35:1387–1399CrossRefGoogle Scholar
  34. Dieli F, Troye-Blomberg M, Farouk SE, Sireci G, Salerno A (2001) Biology of gammadelta T cells in tuberculosis and malaria. Curr Mol Med 1:437–446PubMedCrossRefGoogle Scholar
  35. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF et al (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695PubMedCrossRefGoogle Scholar
  36. Dunn-Walters DK (2016) The ageing human B cell repertoire: a failure of selection? Clin Exp Immunol 183:50–56PubMedCrossRefGoogle Scholar
  37. Dunn-Walters DK, Ademokun AA (2010) B cell repertoire and ageing. Curr Opin Immunol 22:514–520PubMedCrossRefGoogle Scholar
  38. Dusseaux M, Martin E, Serriari N, Peguillet I, Premel V, Louis D et al (2011) Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117:1250–1259PubMedCrossRefGoogle Scholar
  39. Fagiolo U, Cossarizza A, Santacaterina S, Ortolani C, Monti D, Paganelli R et al (1992) Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people. Ann N Y Acad Sci 663:490–493PubMedCrossRefGoogle Scholar
  40. Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E et al (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375–2378PubMedCrossRefGoogle Scholar
  41. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G et al (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95:2860–2868PubMedGoogle Scholar
  42. Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B et al (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124:487–493PubMedCrossRefGoogle Scholar
  43. Franceschi C, Cossarizza A (1995) Introduction: the reshaping of the immune system with age. Int Rev Immunol 12:1–4PubMedCrossRefGoogle Scholar
  44. Franceschi C, Monti D, Cossarizza A, Fagnoni F, Passeri G, Sansoni P (1991) Aging, longevity, and cancer: studies in Down’s syndrome and centenarians. Ann N Y Acad Sci 621:428–440PubMedCrossRefGoogle Scholar
  45. Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 16:12–16PubMedCrossRefGoogle Scholar
  46. Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL et al (2008) Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 180:5283–5290PubMedCrossRefGoogle Scholar
  47. Gangemi S, Basile G, Monti D, Merendino RA, Di Pasquale G, Bisignano U et al (2005) Age-related modifications in circulating IL-15 levels in humans. Mediat Inflamm 2005:245–247CrossRefGoogle Scholar
  48. Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG et al (2011) Immunosenescence of human natural killer cells. J Innate Immun 3:337–343PubMedCrossRefGoogle Scholar
  49. Gerli R, Monti D, Bistoni O, Mazzone AM, Peri G, Cossarizza A et al (2000) Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev 121:37–46PubMedCrossRefGoogle Scholar
  50. Ghia P, Prato G, Scielzo C, Stella S, Geuna M, Guida G et al (2004) Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood 103:2337–2342PubMedCrossRefGoogle Scholar
  51. Godfrey DI, Berzins SP (2007) Control points in NKT-cell development. Nat Rev Immunol 7:505–518PubMedCrossRefGoogle Scholar
  52. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231–237PubMedCrossRefGoogle Scholar
  53. Godfrey DI, Stankovic S, Baxter AG (2010) Raising the NKT cell family. Nat Immunol 11:197–206PubMedCrossRefGoogle Scholar
  54. Gombar S, Jung HJ, Dong F, Calder B, Atzmon G, Barzilai N et al (2012) Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing. BMC Genomics 13:353PubMedPubMedCentralCrossRefGoogle Scholar
  55. Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R et al (2005) The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 140:540–546PubMedPubMedCentralCrossRefGoogle Scholar
  56. Griffiths GM (2003) Endocytosing the death sentence. J Cell Biol 160:155–156PubMedPubMedCentralCrossRefGoogle Scholar
  57. Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211:144–156PubMedPubMedCentralCrossRefGoogle Scholar
  58. Haynes L, Linton PJ, Eaton SM, Tonkonogy SL, Swain SL (1999) 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 190:1013–1024PubMedPubMedCentralCrossRefGoogle Scholar
  59. Hintz M, Reichenberg A, Altincicek B, Bahr U, Gschwind RM, Kollas AK et al (2001) Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett 509:317–322PubMedCrossRefGoogle Scholar
  60. Hwang KA, Kim HR, Kang I (2009) Aging and human CD4(+) regulatory T cells. Mech Ageing Dev 130:509–517PubMedPubMedCentralCrossRefGoogle Scholar
  61. Jacobs JM, Cohen A, Ein-Mor E, Stessman J (2014) Gender differences in survival in old age. Rejuvenation Res 17:499–506PubMedCrossRefGoogle Scholar
  62. Jing Y, Gravenstein S, Rao Chaganty N, Chen N, Lyerly KH, Joyce S et al (2007) Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood. Exp Gerontol 42:719–732PubMedCrossRefGoogle Scholar
  63. Kannan S, Kurupati RK, Doyle SA, Freeman GJ, Schmader KE, Ertl HC (2015) BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine. Oncotarget 6:19445–19455PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kaszubowska L, Kaczor JJ, Hak L, Dettlaff-Pokora A, Szarynska M, Kmiec Z (2011) Sensitivity of natural killer cells to activation in the process of ageing is related to the oxidative and inflammatory status of the elderly. J Physiol Pharmacol 62:101–109PubMedGoogle Scholar
  65. Kawano T, Nakayama T, Kamada N, Kaneko Y, Harada M, Ogura N et al (1999) Antitumor cytotoxicity mediated by ligand-activated human V alpha24 NKT cells. Cancer Res 59:5102–5105PubMedGoogle Scholar
  66. 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 173:7481–7489PubMedCrossRefGoogle Scholar
  67. Kim CH, Johnston B, Butcher EC (2002) Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity. Blood 100:11–16PubMedCrossRefGoogle Scholar
  68. Kim HR, Hong MS, Dan JM, Kang I (2006) Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood 107:2855–2862PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD et al (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520–525PubMedCrossRefGoogle Scholar
  70. Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y et al (1999) The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med 189:1121–1128PubMedPubMedCentralCrossRefGoogle Scholar
  71. Kjer-Nielsen L, Patel O, Corbett AJ, Le Nours J, Meehan B, Liu L et al (2012) MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491:717–723PubMedGoogle Scholar
  72. Koch S, Solana R, Dela Rosa O, Pawelec G (2006) Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev 127:538–543PubMedCrossRefGoogle Scholar
  73. Kutza J, Murasko DM (1994) Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-alpha. Cell Immunol 155:195–204PubMedCrossRefGoogle Scholar
  74. Le Bourhis L, Martin E, Peguillet I, Guihot A, Froux N, Core M et al (2010) Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol 11:701–708PubMedCrossRefGoogle Scholar
  75. Le Bourhis L, Guerri L, Dusseaux M, Martin E, Soudais C, Lantz O (2011) Mucosal-associated invariant T cells: unconventional development and function. Trends Immunol 32:212–218PubMedCrossRefGoogle Scholar
  76. Le Bourhis L, Mburu YK, Lantz O (2013) MAIT cells, surveyors of a new class of antigen: development and functions. Curr Opin Immunol 25:174–180PubMedCrossRefGoogle Scholar
  77. Lee OJ, Cho YN, Kee SJ, Kim MJ, Jin HM, Lee SJ et al (2014) Circulating mucosal-associated invariant T cell levels and their cytokine levels in healthy adults. Exp Gerontol 49:47–54PubMedCrossRefGoogle Scholar
  78. Linsen L, Somers V, Stinissen P (2005) Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol 66:1193–1202PubMedCrossRefGoogle Scholar
  79. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139PubMedCrossRefGoogle Scholar
  80. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217PubMedPubMedCentralCrossRefGoogle Scholar
  81. Lugli E, Pinti M, Nasi M, Troiano L, Ferraresi R, Mussi C et al (2007) Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data. Cytometry A 71:334–344PubMedCrossRefGoogle Scholar
  82. Lutz CT, Moore MB, Bradley S, Shelton BJ, Lutgendorf SK (2005) Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev 126:722–731PubMedPubMedCentralCrossRefGoogle Scholar
  83. Ma A, Koka R, Burkett P (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24:657–679PubMedCrossRefGoogle Scholar
  84. Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E (2013) The who’s who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol 43:2797–2809PubMedCrossRefGoogle Scholar
  85. Mariani E, Monaco MC, Cattini L, Sinoppi M, Facchini A (1994) Distribution and lytic activity of NK cell subsets in the elderly. Mech Ageing Dev 76:177–187PubMedCrossRefGoogle Scholar
  86. Mariani E, Sgobbi S, Meneghetti A, Tadolini M, Tarozzi A, Sinoppi M et al (1996) Perforins in human cytolytic cells: the effect of age. Mech Ageing Dev 92:195–209PubMedCrossRefGoogle Scholar
  87. Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F et al (1999) Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians. Clin Exp Immunol 116:19–27PubMedPubMedCentralCrossRefGoogle Scholar
  88. Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P, Cattini L et al (2002) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol 32:1524–1529PubMedCrossRefGoogle Scholar
  89. Mariotti S, Sansoni P, Barbesino G, Caturegli P, Monti D, Cossarizza A et al (1992) Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet 339:1506–1508PubMedCrossRefGoogle Scholar
  90. Marrie TJ (2000) Community-acquired pneumonia in the elderly. Clin Infect Dis 31:1066–1078PubMedCrossRefGoogle Scholar
  91. Martin F, Kearney JF (2001) B1 cells: similarities and differences with other B cell subsets. Curr Opin Immunol 13:195–201PubMedCrossRefGoogle Scholar
  92. Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413–2417PubMedCrossRefGoogle Scholar
  93. Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529PubMedCrossRefGoogle Scholar
  94. Merino J, Martinez-Gonzalez MA, Rubio M, Inoges S, Sanchez-Ibarrola A, Subira ML (1998) Progressive decrease of CD8high+ CD28+ CD57− cells with ageing. Clin Exp Immunol 112:48–51PubMedPubMedCentralCrossRefGoogle Scholar
  95. Merlini G, Farhangi M, Osserman EF (1986) Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias. Semin Oncol 13:350–365PubMedGoogle Scholar
  96. Miyaji C, Watanabe H, Minagawa M, Toma H, Kawamura T, Nohara Y et al (1997) Numerical and functional characteristics of lymphocyte subsets in centenarians. J Clin Immunol 17:420–429PubMedCrossRefGoogle Scholar
  97. Miyaji C, Watanabe H, Toma H, Akisaka M, Tomiyama K, Sato Y et al (2000) Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians. Hum Immunol 61:908–916PubMedCrossRefGoogle Scholar
  98. Mocchegiani E, Malavolta M (2004) NK and NKT cell functions in immunosenescence. Aging Cell 3:177–184PubMedCrossRefGoogle Scholar
  99. Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N, Franceschi C et al (2003) Metallothioneins/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply. Mech Ageing Dev 124:459–468PubMedCrossRefGoogle Scholar
  100. Molling JW, Kolgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH et al (2005) Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer 116:87–93PubMedCrossRefGoogle Scholar
  101. Mondello C, Petropoulou C, Monti D, Gonos ES, Franceschi C, Nuzzo F (1999) Telomere length in fibroblasts and blood cells from healthy centenarians. Exp Cell Res 248:234–242PubMedCrossRefGoogle Scholar
  102. Monti D, Salvioli S, Capri M, Malorni W, Straface E, Cossarizza A et al (2000) Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians. Mech Ageing Dev 121:239–250PubMedCrossRefGoogle Scholar
  103. Morita CT, Mariuzza RA, Brenner MB (2000) Antigen recognition by human gamma delta T cells: pattern recognition by the adaptive immune system. Springer Semin Immunopathol 22:191–217PubMedCrossRefGoogle Scholar
  104. Moser B, Eberl M (2007) gammadelta T cells: novel initiators of adaptive immunity. Immunol Rev 215:89–102PubMedCrossRefGoogle Scholar
  105. Murasko DM, Jiang J (2005) Response of aged mice to primary virus infections. Immunol Rev 205:285–296PubMedCrossRefGoogle Scholar
  106. Mysliwska J, Trzonkowski P, Szmit E, Brydak LB, Machala M, Mysliwski A (2004) Immunomodulating effect of influenza vaccination in the elderly differing in health status. Exp Gerontol 39:1447–1458PubMedCrossRefGoogle Scholar
  107. Nanno M, Shiohara T, Yamamoto H, Kawakami K, Ishikawa H (2007) gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. Immunol Rev 215:103–113PubMedCrossRefGoogle Scholar
  108. Napier RJ, Adams EJ, Gold MC, Lewinsohn DM (2015) The role of mucosal associated invariant T cells in antimicrobial immunity. Front Immunol 6:344PubMedPubMedCentralCrossRefGoogle Scholar
  109. Nasi M, Troiano L, Lugli E, Pinti M, Ferraresi R, Monterastelli E et al (2006) Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 5:167–175PubMedCrossRefGoogle Scholar
  110. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E et al (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174:7446–7452PubMedCrossRefGoogle Scholar
  111. Nociari MM, Telford W, Russo C (1999) Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naive phenotype. J Immunol 162:3327–3335PubMedGoogle Scholar
  112. Novak J, Dobrovolny J, Novakova L, Kozak T (2014) The decrease in number and change in phenotype of mucosal-associated invariant T cells in the elderly and differences in men and women of reproductive age. Scand J Immunol 80:271–275PubMedCrossRefGoogle Scholar
  113. O’Reilly V, Zeng SG, Bricard G, Atzberger A, Hogan AE, Jackson J et al (2011) Distinct and overlapping effector functions of expanded human CD4+, CD8alpha+ and CD4-CD8alpha- invariant natural killer T cells. PLoS One 6:e28648PubMedPubMedCentralCrossRefGoogle Scholar
  114. Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N et al (2001) Association between natural killer cell activity and infection in immunologically normal elderly people. Clin Exp Immunol 124:392–397PubMedPubMedCentralCrossRefGoogle Scholar
  115. Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121:187–201PubMedCrossRefGoogle Scholar
  116. Onyema OO, Njemini R, Forti LN, Bautmans I, Aerts JL, De Waele M et al (2015) Aging-associated subpopulations of human CD8+ T-lymphocytes identified by their CD28 and CD57 phenotypes. Arch Gerontol Geriatr 61:494–502PubMedCrossRefGoogle Scholar
  117. Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S et al (2003) Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol 38:911–920PubMedCrossRefGoogle Scholar
  118. Paganelli R, Quinti I, Fagiolo U, Cossarizza A, Ortolani C, Guerra E et al (1992) Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population. Clin Exp Immunol 90:351–354PubMedPubMedCentralCrossRefGoogle Scholar
  119. Paolisso G, Barbieri M, Bonafe M, Franceschi C (2000) Metabolic age modelling: the lesson from centenarians. Eur J Clin Investig 30:888–894CrossRefGoogle Scholar
  120. Pawelec G, Solana R, Remarque E, Mariani E (1998) Impact of aging on innate immunity. J Leukoc Biol 64:703–712PubMedCrossRefGoogle Scholar
  121. Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268PubMedCrossRefGoogle Scholar
  122. Peralbo E, Delarosa O, Gayoso I, Pita ML, Tarazona R, Solana R (2006) Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly. Biogerontology 7:483–492PubMedCrossRefGoogle Scholar
  123. Pido-Lopez J, Imami N, Aspinall R (2001) Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin Exp Immunol 125:409–413PubMedPubMedCentralCrossRefGoogle Scholar
  124. Pillai S, Cariappa A, Moran ST (2005) Marginal zone B cells. Annu Rev Immunol 23:161–196PubMedCrossRefGoogle Scholar
  125. Pinti M, Troiano L, Nasi M, Moretti L, Monterastelli E, Mazzacani A et al (2002) Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians. Cell Death Differ 9:431–438PubMedCrossRefGoogle Scholar
  126. Pinti M, Nasi M, Lugli E, Gibellini L, Bertoncelli L, Roat E et al (2010) T cell homeostasis in centenarians: from the thymus to the periphery. Curr Pharm Des 16:597–603PubMedCrossRefGoogle Scholar
  127. Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D et al (2014) Circulating mitochondrial DNA increases with age and is a familiar trait: implications for “inflamm-aging”. Eur J Immunol 44:1552–1562PubMedCrossRefGoogle Scholar
  128. Pinti M, Appay V, Campisi J, Frasca D, Fulop T, Sauce D et al (2016) Aging of the immune system: focus on inflammation and vaccination. Eur J Immunol 46:2286–2301PubMedPubMedCentralCrossRefGoogle Scholar
  129. Pulko V, Davies JS, Martinez C, Lanteri MC, Busch MP, Diamond MS et al (2016) Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat Immunol 17:966–975PubMedPubMedCentralCrossRefGoogle Scholar
  130. Rahimpour A, Koay HF, Enders A, Clanchy R, Eckle SB, Meehan B et al (2015) Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J Exp Med 212:1095–1108PubMedPubMedCentralCrossRefGoogle Scholar
  131. Ramsburg E, Tigelaar R, Craft J, Hayday A (2003) Age-dependent requirement for gammadelta T cells in the primary but not secondary protective immune response against an intestinal parasite. J Exp Med 198:1403–1414PubMedPubMedCentralCrossRefGoogle Scholar
  132. Reade MC, Yende S, D’Angelo G, Kong L, Kellum JA, Barnato AE et al (2009) Differences in immune response may explain lower survival among older men with pneumonia. Crit Care Med 37:1655–1662PubMedPubMedCentralCrossRefGoogle Scholar
  133. Riddell NE, Griffiths SJ, Rivino L, King DC, Teo GH, Henson SM et al (2015) Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults. Immunology 144:549–560PubMedPubMedCentralCrossRefGoogle Scholar
  134. Rink L, Cakman I, Kirchner H (1998) Altered cytokine production in the elderly. Mech Ageing Dev 102:199–209PubMedCrossRefGoogle Scholar
  135. Rodriguez-Perea AL, Arcia ED, Rueda CM, Velilla PA (2016) Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol 185:281–291PubMedPubMedCentralCrossRefGoogle Scholar
  136. Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM et al (2007) Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol 178:4112–4119PubMedCrossRefGoogle Scholar
  137. Rukavina D, Laskarin G, Rubesa G, Strbo N, Bedenicki I, Manestar D et al (1998) Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood 92:2410–2420PubMedGoogle Scholar
  138. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787PubMedCrossRefGoogle Scholar
  139. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712PubMedCrossRefGoogle Scholar
  140. Sandberg JK, Bhardwaj N, Nixon DF (2003) Dominant effector memory characteristics, capacity for dynamic adaptive expansion, and sex bias in the innate Valpha24 NKT cell compartment. Eur J Immunol 33:588–596PubMedCrossRefGoogle Scholar
  141. Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Schroll M, Jeune B (2003) High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes. Gerontology 49:155–160PubMedCrossRefGoogle Scholar
  142. Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D et al (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82:2767–2773PubMedGoogle Scholar
  143. Sansoni P, Fagnoni F, Vescovini R, Mazzola M, Brianti V, Bologna G et al (1997) T lymphocyte proliferative capability to defined stimuli and costimulatory CD28 pathway is not impaired in healthy centenarians. Mech Ageing Dev 96:127–136PubMedCrossRefGoogle Scholar
  144. Schmitt V, Rink L, Uciechowski P (2013) The Th17/Treg balance is disturbed during aging. Exp Gerontol 48:1379–1386PubMedCrossRefGoogle Scholar
  145. Schwab R, Walters CA, Weksler ME (1989) Host defense mechanisms and aging. Semin Oncol 16:20–27PubMedGoogle Scholar
  146. Sciammas R, Bluestone JA (1999) TCRgammadelta cells and viruses. Microbes Infect 1:203–212PubMedCrossRefGoogle Scholar
  147. Scola L, Candore G, Colonna-Romano G, Crivello A, Forte GI, Paolisso G et al (2005) Study of the association with -330T/G IL-2 in a population of centenarians from centre and south Italy. Biogerontology 6:425–429PubMedCrossRefGoogle Scholar
  148. Scotet E, Martinez LO, Grant E, Barbaras R, Jeno P, Guiraud M et al (2005) Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71–80PubMedCrossRefGoogle Scholar
  149. Seino K, Taniguchi M (2004) Functional roles of NKT cell in the immune system. Front Biosci 9:2577–2587PubMedCrossRefGoogle Scholar
  150. Serriari NE, Eoche M, Lamotte L, Lion J, Fumery M, Marcelo P et al (2014) Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin Exp Immunol 176:266–274PubMedPubMedCentralCrossRefGoogle Scholar
  151. Sgarbi G, Matarrese P, Pinti M, Lanzarini C, Ascione B, Gibellini L et al (2014) Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany NY) 6:296–310CrossRefGoogle Scholar
  152. Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L et al (2002) Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections. Science 295:2255–2258PubMedPubMedCentralCrossRefGoogle Scholar
  153. Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K (2005) Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol 175:3262–3267PubMedCrossRefGoogle Scholar
  154. Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, Pereira P et al (2005) Antigen recognition determinants of gammadelta T cell receptors. Science 308:252–255PubMedCrossRefGoogle Scholar
  155. Siegrist CA, Aspinall R (2009) B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 9:185–194PubMedCrossRefGoogle Scholar
  156. Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620PubMedCrossRefGoogle Scholar
  157. Straub RH, Cutolo M (2001) Involvement of the hypothalamic – pituitary – adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum 44:493–507PubMedCrossRefGoogle Scholar
  158. Swain S, Clise-Dwyer K, Haynes L (2005) Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol 17:370–377PubMedPubMedCentralCrossRefGoogle Scholar
  159. Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H (2003) The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol 21:483–513PubMedCrossRefGoogle Scholar
  160. Team WHOER, Agua-Agum J, Ariyarajah A, Blake IM, Cori A, Donnelly CA et al (2015) Ebola virus disease among children in West Africa. N Engl J Med 372:1274–1277CrossRefGoogle Scholar
  161. Trapani JA (1998) Dual mechanisms of apoptosis induction by cytotoxic lymphocytes. Int Rev Cytol 182:111–192PubMedCrossRefGoogle Scholar
  162. Treiner E, Duban L, Bahram S, Radosavljevic M, Wanner V, Tilloy F et al (2003) Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422:164–169PubMedCrossRefGoogle Scholar
  163. Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK et al (2003) Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 74:296–308PubMedCrossRefGoogle Scholar
  164. Vadasz Z, Haj T, Kessel A, Toubi E (2013) Age-related autoimmunity. BMC Med 11:94PubMedPubMedCentralCrossRefGoogle Scholar
  165. van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA et al (2014) Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol 60:190–196PubMedCrossRefGoogle Scholar
  166. Van Kaer L, Parekh VV, Wu L (2011) Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res 343:43–55PubMedCrossRefGoogle Scholar
  167. Vescovini R, Telera A, Fagnoni FF, Biasini C, Medici MC, Valcavi P et al (2004) Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 39:1233–1243PubMedCrossRefGoogle Scholar
  168. Wack A, Cossarizza A, Heltai S, Barbieri D, D’Addato S, Fransceschi C et al (1998) Age-related modifications of the human alphabeta T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets. Int Immunol 10:1281–1288PubMedCrossRefGoogle Scholar
  169. Walker LJ, Tharmalingam H, Klenerman P (2014) The rise and fall of MAIT cells with age. Scand J Immunol 80:462–463PubMedPubMedCentralCrossRefGoogle Scholar
  170. Wallace DL, Zhang Y, Ghattas H, Worth A, Irvine A, Bennett AR et al (2004) Direct measurement of T cell subset kinetics in vivo in elderly men and women. J Immunol 173:1787–1794PubMedCrossRefGoogle Scholar
  171. Wen Z, Shimojima Y, Shirai T, Li Y, Ju J, Yang Z et al (2016) NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs. J Clin Invest 126:1953–1967PubMedPubMedCentralCrossRefGoogle Scholar
  172. Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren 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 60:556–565PubMedCrossRefGoogle Scholar
  173. Wistuba-Hamprecht K, Frasca D, Blomberg B, Pawelec G, Derhovanessian E (2013) Age-associated alterations in gammadelta T-cells are present predominantly in individuals infected with Cytomegalovirus. Immun Ageing 10:26PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Elena Bianchini
    • 1
  • Simone Pecorini
    • 2
  • Sara De Biasi
    • 3
  • Lara Gibellini
    • 1
  • Milena Nasi
    • 1
  • Andrea Cossarizza
    • 4
    Email author
  • Marcello Pinti
    • 5
  1. 1.Department of Surgery, Medicine, Dentistry and Morphological SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  2. 2.Department of Biomedical, Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  3. 3.Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  4. 4.Department of Medical and Surgical Sciences of Children and AdultsUniversity of Modena and Reggio EmiliaModenaItaly
  5. 5.Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly

Section editors and affiliations

  • Tamas Fulop
    • 1
  1. 1.Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of MedicineUniversity of SherbrookeSherbrookeCanada

Personalised recommendations