Lymphocytes Sub-Types and Functions in Centenarians as Models for Successful Ageing

  • Enrico Lugli
  • Leonarda Troiano
  • Marcello Pinti
  • Milena Nasi
  • Erika Roat
  • Roberta Ferraresi
  • Linda Bertoncelli
  • Lara Gibellini
  • Elisa Nemes
  • Andrea Cossarizza


Several cell subsets participate to the immune response, and their close interplay is fundamental for the successful elimination of harmful pathogens. In addition, a tight regulation of the immune response has to occur in order to avoid excessive inflammation and potential autoreactivity towards self components. In the last years, the discovery and the characterization of new lymphocytes subsets, including regulatory T (Treg)-cells and Natural Killer T (NKT)-cells allowed a better understanding of how an effector immune response is induced and therefore down-modulated. During the ageing of the immune system, a process termed immunosenescence, these subsets undergo a profound remodelling, both in phenotype and function. In this chapter, we will describe the essential features of lymphocyte populations in centenarians and the differences that occur with unsuccessfully aged people.


Treg Cell Curr Opin Immunol Natural Killer Cell Number Thymic Activity Polychromatic Flow Cytometry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Franceschi C, Cossarizza A (1995) Introduction: the reshaping of the immune system with age. Int Rev Immunol, 12:1–4sPubMedCrossRefGoogle Scholar
  2. 2.
    Allman D, Miller JP (2005) B-cell development and receptor diversity during aging. Curr Opin Immunol, 17:463–467PubMedGoogle Scholar
  3. 3.
    Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol, 5:133–139PubMedCrossRefGoogle Scholar
  4. 4.
    Wack A, Cossarizza A, Heltai S, Barbieri D, D’Addato S, Fransceschi C, Dellabona P, Casorati G (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
  5. 5.
    Crawford J, Eye MK, Cohen HJ (1987) Evaluation of monoclonal gammopathies in the “well” elderly. Am J Med, 82:39–45PubMedCrossRefGoogle Scholar
  6. 6.
    Mariotti S, Sansoni P, Barbesino G, Caturegli P, Monti D, Cossarizza A, Giacomelli T, Passeri G, Fagiolo U, Pinchera A, et al (1992) Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet, 339:1506–1508PubMedCrossRefGoogle Scholar
  7. 7.
    Goronzy JJ, Weyand CM (2005) T-cell development and receptor diversity during aging. Curr Opin Immunol, 17:468–475PubMedGoogle Scholar
  8. 8.
    Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M (1999) Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol, 34:911–921PubMedCrossRefGoogle Scholar
  9. 9.
    Franceschi C, Bonafe M, Valensin S (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine, 18:1717–1720PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    George AJ, Ritter MA (1996) Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today, 17:267–272PubMedCrossRefGoogle Scholar
  12. 12.
    Steinmann GG, Klaus B, Muller-Hermelink HK (1985) The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol, 22:563–575PubMedCrossRefGoogle Scholar
  13. 13.
    Terszowski G, Muller SM, Bleul CC, Blum C, Schirmbeck R, Reimann J, Pasquier LD, Amagai T, Boehm T, Rodewald HR (2006) Evidence for a functional second thymus in mice. Science, 312:284–287PubMedCrossRefGoogle Scholar
  14. 14.
    Swain S, Clise-Dwyer K, Haynes L (2005) Homeostasis and the age-associated defect of CD4 T-cells. Semin Immunol, 17:370–377PubMedCrossRefGoogle Scholar
  15. 15.
    Kronenberg M, Rudensky A (2005) Regulation of immunity by self-reactive T-cells. Nature, 435:598–604PubMedCrossRefGoogle Scholar
  16. 16.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T-cells in immunological tolerance to self and non-self. Nat Immunol, 6:345–352PubMedCrossRefGoogle Scholar
  17. 17.
    von Boehmer H (2005) Mechanisms of suppression by suppressor T-cells. Nat Immunol, 6:338–344CrossRefGoogle Scholar
  18. 18.
    Ziegler SF (2006) FOXP3: of mice and men. Annu Rev Immunol, 24:209–226PubMedCrossRefGoogle Scholar
  19. 19.
    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rotzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood, 110:1225–1232PubMedCrossRefGoogle Scholar
  20. 20.
    Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, Schmitt E (2007) Cyclic adenosine monophosphate is a key component of regulatory T-cell-mediated suppression. J Exp Med, 204:1303–1310PubMedCrossRefGoogle Scholar
  21. 21.
    Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T-cells mediates immune suppression. J Exp Med, 204:1257–1265PubMedCrossRefGoogle Scholar
  22. 22.
    Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B (2006) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T-cells. J Exp Med, 203:1693–1700PubMedCrossRefGoogle Scholar
  23. 23.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med, 203:1701–1711PubMedCrossRefGoogle Scholar
  24. 24.
    Dejaco C, Duftner C, Schirmer M (2006) Are regulatory T-cells linked with aging? Exp Gerontol, 41:339–345PubMedCrossRefGoogle Scholar
  25. 25.
    Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naïve T-cells. J Exp Med, 199:1401–1408PubMedCrossRefGoogle Scholar
  26. 26.
    Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T-cell populations by foreign antigen. Nat Immunol, 6:1219–1227PubMedCrossRefGoogle Scholar
  27. 27.
    Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, Serio M, Ferrannini E (2006) Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing. Cytokine, 34:32–38PubMedCrossRefGoogle Scholar
  28. 28.
    Begley L, Monteleon C, Shah RB, Macdonald JW, Macoska JA (2005) CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro. Aging Cell, 4:291–298PubMedCrossRefGoogle Scholar
  29. 29.
    Fagiolo U, Cossarizza A, Santacaterina S, Ortolani C, Monti D, Paganelli R, Franceschi C (1992) Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people. Ann N Y Acad Sci, 663:490–493PubMedCrossRefGoogle Scholar
  30. 30.
    Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol, 23:2375–2378PubMedCrossRefGoogle Scholar
  31. 31.
    Gerli R, Monti D, Bistoni O, Mazzone AM, Peri G, Cossarizza A, Di Gioacchino M, Cesarotti ME, Doni A, Mantovani A, Franceschi C, Paganelli R (2000) Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev, 121:37–46PubMedCrossRefGoogle Scholar
  32. 32.
    Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol, 164:2180–2187PubMedGoogle Scholar
  33. 33.
    Cossarizza A, Ortolani C, Monti D, Franceschi C (1997) Cytometric analysis of immunosenescence. Cytometry, 27:297–313PubMedCrossRefGoogle Scholar
  34. 34.
    Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today, 16:12–16PubMedCrossRefGoogle Scholar
  35. 35.
    Paolisso G, Barbieri M, Bonafe M, Franceschi C (2000) Metabolic age modelling: the lesson from centenarians. Eur J Clin Invest, 30:888–894PubMedCrossRefGoogle Scholar
  36. 36.
    Cancro MP (2005) B-cells and aging: gauging the interplay of generative, selective, and homeostatic events. Immunol Rev, 205:48–59PubMedCrossRefGoogle Scholar
  37. 37.
    Lopes-Carvalho T, Foote J, Kearney JF (2005) Marginal zone B-cells in lymphocyte activation and regulation. Curr Opin Immunol, 17:244–250PubMedCrossRefGoogle Scholar
  38. 38.
    Pillai S, Cariappa A, Moran ST (2005) Marginal zone B cells. Annu Rev Immunol, 23:161–196PubMedCrossRefGoogle Scholar
  39. 39.
    Boumsell L, Bernard A, Lepage V, Degos L, Lemerle J, Dausset J (1978) Some chronic lymphocytic leukemia cells bearing surface immunoglobulins share determinants with T-cells. Eur J Immunol, 8:900–904PubMedCrossRefGoogle Scholar
  40. 40.
    Hayakawa K, Hardy RR, Parks DR, Herzenberg LA (1983) The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med, 157:202–218PubMedCrossRefGoogle Scholar
  41. 41.
    Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol, 20:253–300PubMedCrossRefGoogle Scholar
  42. 42.
    Maurer D, Holter W, Majdic O, Fischer GF, Knapp W (1990) CD27 expression by a distinct subpopulation of human B-lymphocytes. Eur J Immunol, 20:2679–2684PubMedCrossRefGoogle Scholar
  43. 43.
    Maurer D, Fischer GF, Fae I, Majdic O, Stuhlmeier K, Von Jeney N, Holter W, Knapp W (1992) IgM and IgG but not cytokine secretion is restricted to the CD27+ B-lymphocyte subset. J Immunol, 148:3700–3705PubMedGoogle Scholar
  44. 44.
    Agematsu K (2000) Memory B-cells and CD27. Histol Histopathol, 15:573–576PubMedGoogle Scholar
  45. 45.
    Agematsu K, Hokibara S, Nagumo H, Komiyama A (2000) CD27: a memory B-cell marker. Immunol Today, 21:204–206PubMedCrossRefGoogle Scholar
  46. 46.
    Agematsu K, Kobata T, Sugita K, Freeman GJ, Beckmann MP, Schlossman SF, Morimoto C (1994)_ Role of CD27 in T-cell immune response. Analysis by recombinant soluble CD27. J Immunol, 153:1421–1429PubMedGoogle Scholar
  47. 47.
    Agematsu K, Nagumo H, Yang FC, Nakazawa T, Fukushima K, Ito S, Sugita K, Mori T, Kobata T, Morimoto C, Komiyama A (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
  48. 48.
    Shi Y, Agematsu K, Ochs HD, Sugane K (2003) Functional analysis of human memory B-cell subpopulations: IgD+CD27+ B-cells are crucial in secondary immune response by producing high affinity IgM. Clin Immunol, 108:128–137PubMedCrossRefGoogle Scholar
  49. 49.
    Paganelli R, Quinti I, Fagiolo U, Cossarizza A, Ortolani C, Guerra E, Sansoni P, Pucillo LP, Scala E, Cozzi E, et al (1992) Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population. Clin Exp Immunol, 90:351–354.PubMedGoogle Scholar
  50. 50.
    Colonna-Romano G, Aquino A, Bulati M, Di Lorenzo G, Listi F, Vitello S, Lio D, Candore G, Clesi G, Caruso C (2006) Memory B-cell subpopulations in the aged. Rejuvenation Res, 9:149–152PubMedCrossRefGoogle Scholar
  51. 51.
    Colonna-Romano G, Bulati M, Aquino A, Scialabba G, Candore G, Lio D, Motta M, Malaguarnera M, Caruso C (2003) B-cells in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev, 124:389–393PubMedCrossRefGoogle Scholar
  52. 52.
    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, 175:3262–3267PubMedGoogle Scholar
  53. 53.
    LeMaoult J, Manavalan JS, Dyall R, Szabo P, Nikolic-Zugic J, Weksler ME (1999) Cellular basis of B-cell clonal populations in old mice. J Immunol, 162:6384–6391PubMedGoogle Scholar
  54. 54.
    Kyle RA, Rajkumar SV (1999) Monoclonal gammopathies of undetermined significance. Hematol Oncol Clin North Am, 13:1181–1202PubMedCrossRefGoogle Scholar
  55. 55.
    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
  56. 56.
    Ghia P, Prato G, Scielzo C, Stella S, Geuna M, Guida G, Caligaris-Cappio F (2004) Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood, 103:2337–2342PubMedCrossRefGoogle Scholar
  57. 57.
    Schwab R, Walters CA, Weksler ME (1989) Host defense mechanisms and aging. Semin Oncol, 16:20–27PubMedGoogle Scholar
  58. 58.
    Rowley MJ, Buchanan H, Mackay IR (1968) Reciprocal change with age in antibody to extrinsic and intrinsic antigens. Lancet, 2:24–26PubMedCrossRefGoogle Scholar
  59. 59.
    Hallgren HM, Buckley CE 3rd, Gilbertsen VA, et al (1973) Lymphocyte phytohemagglutinin responsiveness, immunoglobulins and autoantibodies in aging humans. J Immunol, 111:1101–1107PubMedGoogle Scholar
  60. 60.
    De Greef GE, Van Tol MJ, Van Den Berg JW, Van Staalduinen GJ, Janssen CJ, Radl J, Hijmans W. (1992) Serum immunoglobulin class and IgG subclass levels and the occurrence of homogeneous immunoglobulins during the course of ageing in humans. Mech Ageing Dev, 66:29–44PubMedCrossRefGoogle Scholar
  61. 61.
    Listi F, Candore G, Modica MA, Russo M, Di Lorenzo G, Esposito-Pellitteri M, Colonna- Romano G, Aquino A, Bulati M, Lio D, Franceschi C, Caruso C (2006) A study of serum immunoglobulin levels in elderly persons that provides new insights into B-cell immunosenescence. Ann N Y Acad Sci, 1089:487–495PubMedCrossRefGoogle Scholar
  62. 62.
    Cossarizza A, Ortolani C, Paganelli R Barbieri D, Monti D, Sansoni P, Fagiolo U, Castellani G, Bersani F, Londei M, Franceschi C (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
  63. 63.
    Miller RA (1996) The aging immune system: primer and prospectus. Science, 273:70–74PubMedCrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Okumura M, Fujii Y, Takeuchi Y, Inada K, Nakahara K, Matsuda H (1993) Age-related accumulation of LFA-1high cells in a CD8+CD45RAhigh T-cell population. Eur J Immunol, 23:1057–1063PubMedCrossRefGoogle Scholar
  66. 66.
    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
  67. 67.
    Lanzavecchia A, Sallusto F (2005) Understanding the generation and function of memory T-cell subsets. Curr Opin Immunol, 17:326–332PubMedCrossRefGoogle Scholar
  68. 68.
    Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8(+) T-cells provides new insights on immunodeficiency in aging. Blood, 95:2860–2868PubMedGoogle Scholar
  69. 69.
    De Rosa SC, Herzenberg LA, Roederer M (2001) 11–color, 13-parameter flow cytometry: identification of human naive T-cells by phenotype, function, and T-cell receptor diversity. Nat Med, 7:245–248PubMedCrossRefGoogle Scholar
  70. 70.
    Lugli E, Pinti M, Nasi M, Troiano L, Ferraresi R, Mussi C, Salvioli G, Patsekin V, Robinson JP, Durante C, Cocchi M, Cossarizza A (2007) Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data. Cytometry A, 71:334–344PubMedGoogle Scholar
  71. 71.
    Nasi M, Troiano L, Lugli E, Pinti M, Ferraresi R, Monterastelli E, Mussi C, Salvioli G, Franceschi C, Cossarizza A (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
  72. 72.
    Hamann D, Kostense S, Wolthers KC, Otto SA, Baars PA, Miedema F, van Lier RA (1999) Evidence that human CD8+CD45RA+CD27–cells are induced by antigen and evolve through extensive rounds of division. Int Immunol, 11:1027–1033PubMedCrossRefGoogle Scholar
  73. 73.
    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, 112:48–51PubMedCrossRefGoogle Scholar
  74. 74.
    Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, Muller CA, Pircher H, Pawelec G (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
  75. 75.
    Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP (2000) The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol, 18:529–560PubMedCrossRefGoogle Scholar
  76. 76.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature, 396:690–695PubMedCrossRefGoogle Scholar
  77. 77.
    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
  78. 78.
    Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity, 9:669–676PubMedCrossRefGoogle Scholar
  79. 79.
    Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ (2000) Reversible defects in natural killer and memory CD8 T-cell lineages in interleukin 15-deficient mice. J Exp Med, 191:771–780PubMedCrossRefGoogle Scholar
  80. 80.
    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, 107:2855–2862PubMedCrossRefGoogle Scholar
  81. 81.
    Gangemi S, Basile G, Monti D, Merendino RA, Di Pasquale G, Bisignano U, Nicita-Mauro V, Franceschi C (2005) Age-related modifications in circulating IL-15 levels in humans. Mediators Inflamm, :245–247Google Scholar
  82. 82.
    Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T-cell generation and TCR diversity. J Immunol, 174:7446–7452PubMedGoogle Scholar
  83. 83.
    Wallace DL, Zhang Y, Ghattas H, Worth A, Irvine A, Bennett AR, Griffin GE, Beverley PC, Tough DF, Macallan DC (2004) Direct measurement of T-cell subset kinetics in vivo in elderly men and women. J Immunol, 173:1787–1794PubMedGoogle Scholar
  84. 84.
    Geginat J, Lanzavecchia A, Sallusto F (2003) Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood, 101:4260–4266PubMedCrossRefGoogle Scholar
  85. 85.
    Weng NP (2006) Aging of the immune system: how much can the adaptive immune system adapt? Immunity, 24:495–499PubMedCrossRefGoogle Scholar
  86. 86.
    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, 190:1013–1024PubMedCrossRefGoogle Scholar
  87. 87.
    Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L (2004) Age-related defects in CD4 T-cell cognate helper function lead to reductions in humoral responses. J Exp Med, 200:1613–1622PubMedCrossRefGoogle Scholar
  88. 88.
    Cossarizza A, Monti D, Bersani F, Paganelli R, Montagnani G, Cadossi R, Cantini M, Franceschi C (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
  89. 89.
    Witkowski JM, Li SP, Gorgas G, Miller RA (1994) Extrusion of the P glycoprotein substrate rhodamine-123 distinguishes CD4 memory T-cell subsets that differ in IL-2-driven IL-4 production. J Immunol, 153:658–665PubMedGoogle Scholar
  90. 90.
    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
  91. 91.
    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
  92. 92.
    Vescovini R, Telera A, Fagnoni FF, Biasini C, Medici MC, Valcavi P, di Pede P, Lucchini G, Zanlari L, Passeri G, Zanni F, Chezzi C, Franceschi C, Sansoni P (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
  93. 93.
    Khan N, Hislop A, Gudgeon N, Cobbold M, Khanna R, Nayak L, Rickinson AB, Moss PA (2004) Herpesvirus-specific CD8 T-cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol, 173:7481–7489PubMedGoogle Scholar
  94. 94.
    Sansoni P, Fagnoni F, Vescovini R, Mazzola M, Brianti V, Bologna G, Nigro E, Lavagetto G, Cossarizza A, Monti D, Franceschi C, Passeri M (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
  95. 95.
    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, 621:428–440.PubMedCrossRefGoogle Scholar
  96. 96.
    Bellavia D, Frada G, Di Franco P, Feo S, Franceschi C, Sansoni P, Brai M (1999) C4, BF, C3 allele distribution and complement activity in healthy aged people and centenarians. A Biol Sci Med Sci, 54:B150–B153Google Scholar
  97. 97.
    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
  98. 98.
    Scola L, Candore G, Colonna-Romano G, Crivello A, Forte GI, Paolisso G, Franceschi C, Lio D, Caruso C (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
  99. 99.
    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
  100. 100.
    Wikby A, Johansson B, Olsson J, Lofgren S, Nilsson BO, Ferguson F (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol, 37:445–453PubMedCrossRefGoogle Scholar
  101. 101.
    Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B (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, 60:556–565PubMedGoogle Scholar
  102. 102.
    Callahan JE, Kappler JW, Marrack P (1993) Unexpected expansions of CD8-bearing cells in old mice. J Immunol, 151:6657–6669PubMedGoogle Scholar
  103. 103.
    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
  104. 104.
    Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, Travers P, Pawelec G (2003) Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J Clin Immunol, 23:247–257PubMedCrossRefGoogle Scholar
  105. 105.
    Akbar AN, Fletcher JM (2005) Memory T-cell homeostasis and senescence during aging. Curr Opin Immunol, 17:480–485.PubMedCrossRefGoogle Scholar
  106. 106.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol, 155:1151–1164PubMedGoogle Scholar
  107. 107.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4 +T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 389:737–742PubMedCrossRefGoogle Scholar
  108. 108.
    Kim JM, Rudensky A (2006) The role of the transcription factor Foxp3 in the development of regulatory T-cells. Immunol Rev, 212:86–98PubMedCrossRefGoogle Scholar
  109. 109.
    Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T-cell lineage. Nat Immunol, 8:457–462PubMedCrossRefGoogle Scholar
  110. 110.
    Bluestone JA, Abbas AK (2003) Natural versus adaptive regulatory T-cells. Nat Rev Immunol, 3:253–257PubMedCrossRefGoogle Scholar
  111. 111.
    Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK, Whitham RH, Bakke A, Jones RE, Offner H, Bourdette DN, Vandenbark AA (2003) Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res, 74:296–308PubMedCrossRefGoogle Scholar
  112. 112.
    Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, Nayak L, Moss PA (2005) The number of human peripheral blood CD4+ CD25high regulatory T-cells increases with age. Clin Exp Immunol, 140:540–546PubMedCrossRefGoogle Scholar
  113. 113.
    Trzonkowski P, Szmit E, Mysliwska J, Mysliwski A (2006) CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK-cells in humans-impact of immunosenescence. Clin Immunol, 119:307–316PubMedCrossRefGoogle Scholar
  114. 114.
    Sharma S, Dominguez AL, Lustgarten J (2006) High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol, 177:8348–8355PubMedGoogle Scholar
  115. 115.
    Nishioka T, Shimizu J, Iida R, Yamazaki S, Sakaguchi S (2006) CD4+CD25+Foxp3+ T-cells and CD4+CD25-Foxp3+ T-cells in aged mice. J Immunol, 176:6586–6593PubMedGoogle Scholar
  116. 116.
    Shimizu J, Moriizumi E (2003) CD4+CD25- T-cells in aged mice are hyporesponsive and exhibit suppressive activity. J Immunol, 170:1675–1682PubMedGoogle Scholar
  117. 117.
    Moser B, Eberl M (2007) gammadelta T-cells: novel initiators of adaptive immunity. Immunol Rev, 215:89–102PubMedCrossRefGoogle Scholar
  118. 118.
    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
  119. 119.
    Hayday AC (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol, 18:975–1026PubMedCrossRefGoogle Scholar
  120. 120.
    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
  121. 121.
    Hintz M, Reichenberg A, Altincicek B, Bahr U, Gschwind RM, Kollas AK, Beck E, Wiesner J, Eberl M, Jomaa H (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
  122. 122.
    Reichenberg A, Hintz M, Kletschek Y, Kuhl T, Haug C, Engel R, Moll J, Ostrovsky DN, Jomaa H, Eberl M (2003) Replacing the pyrophosphate group of HMB-PP by a diphosphonate function abrogates Its potential to activate human gammadelta T-cells but does not lead to competitive antagonism. Bioorg Med Chem Lett, 13:1257–1260PubMedCrossRefGoogle Scholar
  123. 123.
    Scotet E, Martinez LO, Grant E, Barbaras R, Jeno P, Guiraud M, Monsarrat B, Saulquin X, Maillet S, Esteve JP, Lopez F, Perret B, Collet X, Bonneville M, Champagne E (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
  124. 124.
    Chen ZW, Letvin NL (2003) Vgamma2Vdelta2+ T-cells and anti-microbial immune responses. Microbes Infect, 5:491–498PubMedCrossRefGoogle Scholar
  125. 125.
    Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L, Kou Z, Wang Q, Jiang L, Estep J, Hunt R, Clagett M, Sehgal PK, Li Y, Zeng X, Morita CT, Brenner MB, Letvin NL, Chen ZW (2002) Adaptive immune response of Vgamma2Vdelta2+ T-cells during mycobacterial infections. Science, 295:2255–2258PubMedCrossRefGoogle Scholar
  126. 126.
    Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, Pereira P, Chien YH (2005) Antigen recognition determinants of gammadelta T-cell receptors. Science, 308:252–255PubMedCrossRefGoogle Scholar
  127. 127.
    De Rosa SC, Andrus JP, Perfetto SP, Mantovani JJ, Herzenberg LA, Roederer M (2004) Ontogeny of gamma delta T-cells in humans. J Immunol, 172:1637–1645PubMedGoogle Scholar
  128. 128.
    Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science, 291:2413–2417PubMedCrossRefGoogle Scholar
  129. 129.
    Brandes M, Willimann K, Moser B (2005) Professional antigen-presentation function by human gammadelta T-Cells. Science, 309:264–268PubMedCrossRefGoogle Scholar
  130. 130.
    Argentati K, Re F, Donnini A, Tucci MG, Franceschi C, Bartozzi B, Bernardini G, Provinciali M (2002) Numerical and functional alterations of circulating gammadelta T lymphocytes in aged people and centenarians. J Leukoc Biol, 72:65–71PubMedGoogle Scholar
  131. 131.
    Colonna-Romano G, Aquino A, Bulati M, Lio D, Candore G, Oddo G, Scialabba G, Vitello S, Caruso C (2004) Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence. Exp Gerontol, 39:1439–1446PubMedCrossRefGoogle Scholar
  132. 132.
    Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC (2001) Regulation of cutaneous malignancy by gammadelta T-cells. Science, 294:605–609PubMedCrossRefGoogle Scholar
  133. 133.
    Groh V, Steinle A, Bauer S, Spies T (1998) Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T-cells. Science, 279:1737–1740PubMedCrossRefGoogle Scholar
  134. 134.
    Dechanet J, Merville P, Lim A, Retiere C, Pitard V, Lafarge X, Michelson S, Meric C, Hallet MM, Kourilsky P, Potaux L, Bonneville M, Moreau JF (1999) Implication of gammadelta T-cells in the human immune response to cytomegalovirus. J Clin Invest, 103:1437–1449PubMedCrossRefGoogle Scholar
  135. 135.
    Sciammas R, Bluestone JA (1999) TCRgammadelta cells and viruses. Microbes Infect, 1:203–212PubMedCrossRefGoogle Scholar
  136. 136.
    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
  137. 137.
    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, 198:1403–1414PubMedCrossRefGoogle Scholar
  138. 138.
    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
  139. 139.
    Budzynski W, Radzikowski C (1994) Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol, 16:319–346PubMedCrossRefGoogle Scholar
  140. 140.
    Lanier LL, Yu G, Phillips JH (1989) Coassociation of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature, 342:803–805PubMedCrossRefGoogle Scholar
  141. 141.
    Nakazawa T, Agematsu K, Yabuhara A (1997) Later development of Fas ligand-mediated cytotoxicity as compared with granule-mediated cytotoxicity during the maturation of natural killer cells. Immunology, 92:180–187PubMedCrossRefGoogle Scholar
  142. 142.
    Griffiths GM (2003) Endocytosing the death sentence. J Cell Biol, 160:155–156PubMedCrossRefGoogle Scholar
  143. 143.
    Trapani JA (1998) Dual mechanisms of apoptosis induction by cytotoxic lymphocytes. Int Rev Cytol, 182:111–192PubMedCrossRefGoogle Scholar
  144. 144.
    Solana R, Mariani E (2000) NK and NK/T-cells in human senescence. Vaccine, 18:1613–1620PubMedCrossRefGoogle Scholar
  145. 145.
    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
  146. 146.
    Ogata K, Yokose N, Tamura H, An E, Nakamura K, Dan K, Nomura T (1997) Natural killer cells in the late decades of human life. Clin Immunol Immunopathol, 84:269–275PubMedCrossRefGoogle Scholar
  147. 147.
    Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N, Minami S, Dan K (2001) Association between natural killer cell activity and infection in immunologically normal elderly people. Clin Exp Immunol, 124:392–397PubMedCrossRefGoogle Scholar
  148. 148.
    Pawelec G, Solana R, Remarque E, Mariani E (1998) Impact of aging on innate immunity. J Leukoc Biol, 64:703–712PubMedGoogle Scholar
  149. 149.
    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
  150. 150.
    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
  151. 151.
    Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, Marcato A, Passeri G, Ortolani C, Forti E, et al (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood, 82:2767–2773PubMedGoogle Scholar
  152. 152.
    Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R (1999) NK phenotypic markers and IL2 response in NK-cells from elderly people. Exp Gerontol, 34:253–265PubMedCrossRefGoogle Scholar
  153. 153.
    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, 126:722–731PubMedCrossRefGoogle Scholar
  154. 154.
    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
  155. 155.
    Mariani E, Sgobbi S, Meneghetti A, Tadolini M, Tarozzi A, Sinoppi M, Cattini L, Facchini A (1996) Perforins in human cytolytic cells: the effect of age. Mech Ageing Dev, 92:195–209PubMedCrossRefGoogle Scholar
  156. 156.
    Rukavina D, Laskarin G, Rubesa G, Strbo N, Bedenicki I, Manestar D, Glavas M, Christmas SE, Podack ER (1998) Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood, 92:2410–2420PubMedGoogle Scholar
  157. 157.
    Franceschi C, Motta L, Valensin S, Rapisarda R, Franzone A, Berardelli M, Motta M, Monti D, Bonafe M, Ferrucci L, Deiana L, Pes GM, Carru C, Desole MS, Barbi C, Sartoni G, Gemelli C, Lescai F, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Gueresi P, Cossarizza A, Troiano L, Pini G, Sansoni P, Passeri G, Lisa R, Spazzafumo L, Amadio L, Giunta S, Stecconi R, Morresi R, Viticchi C, Mattace R, De Benedictis G, Baggio G (2000) Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano), 12:77–84Google Scholar
  158. 158.
    Rink L, Cakman I, Kirchner H (1998) Altered cytokine production in the elderly. Mech Ageing Dev, 102:199–209PubMedCrossRefGoogle Scholar
  159. 159.
    Murasko DM, Jiang J (2005) Response of aged mice to primary virus infections. Immunol Rev, 205:285–296PubMedCrossRefGoogle Scholar
  160. 160.
    Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P, Cattini L, Facchini A (2002) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol, 32:1524–1529PubMedCrossRefGoogle Scholar
  161. 161.
    Kelley KW, Weigent DA, Kooijman R (2007) Protein hormones and immunity. Brain Behav Immun, 21:384–392PubMedCrossRefGoogle Scholar
  162. 162.
    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
  163. 163.
    Mocchegiani E, Giacconi R, Muti E, Rogo C, Bracci M, Muzzioli M, Cipriano C, Malavolta M (2004) Zinc, immune plasticity, aging, and successful aging: role of metallothionein. Ann N Y Acad Sci, 1019:127–134PubMedCrossRefGoogle Scholar
  164. 164.
    Mocchegiani E, Malavolta M (2004) NK and NKT cell functions in immunosenescence. Aging Cell, 3:177–184PubMedCrossRefGoogle Scholar
  165. 165.
    Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F, Boschi F, Pratelli L, Pizzoferrato A, Piras F, Facchini A (1999) Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians. Clin Exp Immunol, 116:19–27PubMedCrossRefGoogle Scholar
  166. 166.
    Miyaji C, Watanabe H, Toma H, Akisaka M, Tomiyama K, Sato Y, Abo T (2000) Functional alteration of granulocytes, NK-cells, and natural killer T-cells in centenarians. Hum Immunol, 61:908–916PubMedCrossRefGoogle Scholar
  167. 167.
    Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N, Franceschi C, Gaetti R, Cavalieri E, Suzuki H (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
  168. 168.
    Porcelli S, Yockey CE, Brenner MB, Balk SP (1993) Analysis of T-cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T-cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J Exp Med, 178:1–16PubMedCrossRefGoogle Scholar
  169. 169.
    Davodeau F, Peyrat MA, Necker A, Dominici R, Blanchard F, Leget C, Gaschet J, Costa P, Jacques Y, Godard A, Vie H, Poggi A, Romagne F, Bonneville M (1997) Close phenotypic and functional similarities between human and murine alphabeta T-cells expressing invariant TCR alpha-chains. J Immunol, 158:5603–5611PubMedGoogle Scholar
  170. 170.
    Makino Y, Kanno R, Ito T, Higashino K, Taniguchi M (1995) Predominant expression of invariant V alpha 14+ TCR alpha chain in NK1.1+ T-cell populations. Int Immunol, 7:1157–1161PubMedCrossRefGoogle Scholar
  171. 171.
    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
  172. 172.
    Prussin C, Foster B (1997) TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T-cell analog containing a unique Th0 subpopulation. J Immunol, 159:5862–5870PubMedGoogle Scholar
  173. 173.
    Brigl M, Brenner MB (2004) CD1: antigen presentation and T-cell function. Annu Rev Immunol, 22:817–890PubMedCrossRefGoogle Scholar
  174. 174.
    Bendelac A, Rivera MN, Park SH, et al (1997) Mouse CD1-specific NK1 T-cells: development, specificity, and function. Annu Rev Immunol, 15:535–562PubMedCrossRefGoogle Scholar
  175. 175.
    Zhou D, Mattner J, Cantu C, 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004) Lysosomal glycosphingolipid recognition by NKT-cells. Science, 306:1786–1789PubMedCrossRefGoogle Scholar
  176. 176.
    Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M (2005) Recognition of bacterial glycosphingolipids by natural killer T-cells. Nature, 434:520–525PubMedCrossRefGoogle Scholar
  177. 177.
    Zajonc DM, Maricic I, Wu D, Halder R, Roy K, Wong CH, Kumar V, Wilson IA (2005) Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J Exp Med, 202:1517–1526PubMedCrossRefGoogle Scholar
  178. 178.
    Mattner J, Debord KL, Ismail N, Goff RD, Cantu C, 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A (2005) Exogenous and endogenous glycolipid antigens activate NKT-cells during microbial infections. Nature, 434:525–529PubMedCrossRefGoogle Scholar
  179. 179.
    Kim CH, Butcher EC, Johnston B (2002) Distinct subsets of human Valpha24-invariant NKT-cells: cytokine responses and chemokine receptor expression. Trends Immunol, 23:516–519PubMedCrossRefGoogle Scholar
  180. 180.
    Lee PT, Benlagha K, Teyton L, Bendelac A (2002) Distinct functional lineages of human V(alpha)24 natural killer T-cells. J Exp Med, 195:637–641PubMedCrossRefGoogle Scholar
  181. 181.
    Gumperz JE, Miyake S, Yamamura T, Brenner MB (2002) Functionally distinct subsets of CD1d-restricted natural killer T-cells revealed by CD1d tetramer staining. J Exp Meds, 195:625–636CrossRefGoogle Scholar
  182. 182.
    D’Andrea A, Goux D, De Lalla C, Koezuka Y, Montagna D, Moretta A, Dellabona P, Casorati G, Abrignani S (2000) Neonatal invariant Valpha24+ NKT lymphocytes are activated memory cells. Eur J Immunol, 30:1544–1550PubMedCrossRefGoogle Scholar
  183. 183.
    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
  184. 184.
    Godfrey DI, Berzins SP (2007) Control points in NKT-cell development. Nat Rev Immunol, 7:505–518PubMedCrossRefGoogle Scholar
  185. 185.
    Seino K, Taniguchi M (2004) Functional roles of NKT cell in the immune system. Front Biosci, 9:2577–2587PubMedCrossRefGoogle Scholar
  186. 186.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT-cells. J Clin Invest, 114:1379–1388PubMedGoogle Scholar
  187. 187.
    Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nishimura T (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, 189:1121–1128PubMedCrossRefGoogle Scholar
  188. 188.
    Kawano T, Nakayama T, Kamada N, Kaneko Y, Harada M, Ogura N, Akutsu Y, Motohashi S, Iizasa T, Endo H, Fujisawa T, Shinkai H, Taniguchi M (1999) Antitumor cytotoxicity mediated by ligand-activated human V alpha24 NKT-cells. Cancer Res, 59:5102–5105PubMedGoogle Scholar
  189. 189.
    Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of Valpha24+Vbeta11+ NKT-cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood, 103:383–389PubMedCrossRefGoogle Scholar
  190. 190.
    Kronenberg M (2005) Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol, 23:877–900PubMedCrossRefGoogle Scholar
  191. 191.
    Linsen L, Somers V, Stinissen P (2005) Immunoregulation of autoimmunity by natural killer T-cells. Hum Immunol, 66:1193–1202PubMedCrossRefGoogle Scholar
  192. 192.
    MacDonald HR (2002) Development and selection of NKT-cells. Curr Opin Immunol, 14:250–254PubMedCrossRefGoogle Scholar
  193. 193.
    McNerlan SE, Rea IM, Alexander HD, Morris TC (1998) Changes in natural killer cells, the CD57CD8 subset, and related cytokines in healthy aging. J Clin Immunol, 18:31–38PubMedCrossRefGoogle Scholar
  194. 194.
    Miyaji C, Watanabe H, Minagawa M, Toma H, Kawamura T, Nohara Y, Nozaki H, Sato Y, Abo T (1997) Numerical and functional characteristics of lymphocyte subsets in centenarians. J Clin Immunol, 17:420–429PubMedCrossRefGoogle Scholar
  195. 195.
    DelaRosa O, Tarazona R, Casado JG, Alonso C, Ostos B, Pena J, Solana R (2002) Valpha24+NKT-cells are decreased in elderly humans. Exp Gerontol, 37:213–217PubMedCrossRefGoogle Scholar
  196. 196.
    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, 91:1880–1886PubMedCrossRefGoogle Scholar
  197. 197.
    Molling JW, Kolgen W, Van Der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, Molenkamp BG, Langendijk JA, Leemans CR, von Blomberg BM, Scheper RJ, Van Den Eertwegh AJ (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
  198. 198.
    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
  199. 199.
    Jing Y, Gravenstein S, Rao Chaganty N, Chen N, Lyerly KH, Joyce S, Deng Y (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 GerontolGoogle Scholar
  200. 200.
    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
  201. 201.
    Tarazona R, DelaRosa O, Alonso C, Ostos B, Espejo J, Pena J, Solana R (2000) Increased expression of NK cell markers on T-lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T-cells. Mech Ageing Dev, 121:77–88PubMedCrossRefGoogle Scholar
  202. 202.
    Abedin S, Michel JJ, Lemster B, Vallejo AN (2005) Diversity of NKR expression in aging T-cells and in T-cells of the aged: the new frontier into the exploration of protective immunity in the elderly. Exp Gerontol, 40:537–548PubMedCrossRefGoogle Scholar
  203. 203.
    Berzins SP, Uldrich AP, Pellicci DG, McNab F, Hayakawa Y, Smyth MJ, Godfrey DI (2004) Parallels and distinctions between T and NKT cell development in the thymus. Immunol Cell Biol, 82:269–275PubMedCrossRefGoogle Scholar
  204. 204.
    Benlagha K, Wei DG, Veiga J, Teyton L, Bendelac A (2005) Characterization of the early stages of thymic NKT cell development. J Exp Med, 202:485–492PubMedCrossRefGoogle Scholar
  205. 205.
    Egawa T, Eberl G, Taniuchi I, Benlagha K, Geissmann F, Hennighausen L, Bendelac A, Littman DR (2005) Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors. Immunity, 22:705–716PubMedCrossRefGoogle Scholar
  206. 206.
    Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev, 124:487–493PubMedCrossRefGoogle Scholar
  207. 207.
    De Martinis M, Modesti M, Ginaldi L (2004) Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol Cell Biol, 82:415–420PubMedCrossRefGoogle Scholar
  208. 208.
    Perfetto SP, Chattopadhyay PK, Roederer M (2004) Seventeen-colour flow cytometry: unravelling the immune system. Nat Rev Immunol, 4:648–655PubMedCrossRefGoogle Scholar
  209. 209.
    Lugli E, Troiano L, Cossarizza A. Investigating T cells by polychromatic flow cytometry. T cell protocols:Second edition, Vol. 54. G. De Libero Ed. Humana Press, 2009 (in press)Google Scholar
  210. 210.
    Clambey ET, Kappler JW, Marrack P (2007) CD8 T-cell clonal expansions & aging: a heterogeneous phenomenon with a common outcome. Exp Gerontol, 42:407–411PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Enrico Lugli
    • 1
  • Leonarda Troiano
    • 1
  • Marcello Pinti
    • 1
  • Milena Nasi
    • 1
  • Erika Roat
    • 1
  • Roberta Ferraresi
    • 1
  • Linda Bertoncelli
    • 1
  • Lara Gibellini
    • 1
  • Elisa Nemes
    • 1
  • Andrea Cossarizza
    • 1
  1. 1.Chair of Immunology, Department of Biomedical SciencesUniversity of Modena and Reggio EmiliaModenaItaly

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