T-Cell Signalling, a Complex Process for T-Cell Activation Compromised with Aging: When Membrane Rafts Can Simplify Everything

  • Tamas Fulop
  • Graham Pawelec
  • Carl Fortin
  • Anis Larbi
Part of the Medical Intelligence Unit book series (MIUN)


Aging is associated with altered immune responsiveness, termed “immunosenescence”. It is now well accepted that both arms of the immune system, innate as well as adaptive, undergo immunosenescence. However, the adaptive immune response and especially T-cells are the most affected by aging. Aging is associated with both changes in lymphocytes subpopulations and, importantly, functional changes within these subsets. Indeed, T-cells present functional modifications resulting in a decreased clonal expansion and interleukin-2 production as well as a shift in Th1/Th2 response with aging. Identifying alterations in the activation process involving the TCR, CD28 and IL-2 receptor signalling cascades are crucial to understanding immunoseneescence. The putative reasons for this altered activation of T-cells with aging will be reviewed here, based on our own recent work and international collaborations.


Lipid Raft Clonal Expansion Membrane Raft Immune Synapse Plasma Membrane Microdomains 


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  1. 1.
    Pawelec G, Solana R. Immunosenescence. Trends Immunol 1997; 11:514–516.Google Scholar
  2. 2.
    Miller RA. The aging immune system: primers and prospectus. Science 1996; 273:70–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Fulop T, Larbi A, Douziech N et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell 2004; 3:217–226.PubMedCrossRefGoogle Scholar
  4. 4.
    Grubeck-Loebenstein B, Wick G. The aging of the immune system. Adv Immunol 2002; 80:243–284.PubMedCrossRefGoogle Scholar
  5. 5.
    Fulop T, Larbi A, Wikby A et al. Dysregulation of T-cell function in the elderly: scientific basis and clinical implications. Drugs Aging 2005; 22:589–603.PubMedCrossRefGoogle Scholar
  6. 6.
    Fagnoni FF, Vescovini R, Passeri G et al. Shortage of circulating naive CD8(+) T-cells provides new insights on immunodeficiency in aging. Blood 2000; 95:2860–2868.PubMedGoogle Scholar
  7. 7.
    Effros RB. Replicative senescence of CD8 T-cells: effect of human aging. Exp Gerontol 2004; 39:517–524.PubMedCrossRefGoogle Scholar
  8. 8.
    Pawelec G, Akbar A, Caruso C et al. Is immunosenescence infectious? Trends Immunol 2004; 25:406–410.PubMedCrossRefGoogle Scholar
  9. 9.
    Pawelec G, Hirokawa K, Fulop T. T-cell signalling with aging. Mech Age Dev 2001; 122:1613–1637.CrossRefGoogle Scholar
  10. 10.
    Larbi A, Muti E, Giacconi R et al. Role of lipid rafts in activation-induced cell death: the fas pathway in aging. Adv Exp Med Biol 2006; 584:137–55.PubMedCrossRefGoogle Scholar
  11. 11.
    Gupta S. Molecular and biochemical pathways of apoptosis in lymphocytes and aged humans. Vaccine 2000; 18:1596–1601.PubMedCrossRefGoogle Scholar
  12. 12.
    Messaoudi I, Warner J, Nikolich-Zugich N et al. Molecular, cellular and antigen requirements for development of age-associated T-cell clonal expansions in vivo. J Immunol 2006; 173:301–308.Google Scholar
  13. 13.
    Douziech N, Serers I, Larbi A et al. Modulation of human lymphocyte proliferative response with aging. Exp Gerontol 2002; 37:369–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Brzezinska A, Magalska A, Szybinska A et al. Proliferation and apoptosis of human CD8(+)CD28(+) and CD8(+)CD28() lymphocytes during aging. Exp Gerontol 2004; 39:539–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Nel AE, Slaughter N. T-cell activation through the antigen receptor. Part 2: role of signaling cascades in T-cell differentiation, anergy, immune senescence and development of immunotherapy. J Allergy Clin Immunol 2002; 109:901–915.PubMedCrossRefGoogle Scholar
  16. 16.
    Thomas RM, Gao L, Wells AD. Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. J Immunol 2005; 174:4639–46.PubMedGoogle Scholar
  17. 17.
    Thewisen M, Linsen L, Somers V et al. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann N Y Acad Sci 2005; 1051:255–62.CrossRefGoogle Scholar
  18. 18.
    Ouyang Q, Wagner WM, Vochringer D et al. Age-associated accumulation of CMV-specific CD8+ T-cells expressing the killer cell lectine-like receptor G1 (KLRG-1). Exp Gerontol 2003; 38:911–920.PubMedCrossRefGoogle Scholar
  19. 19.
    De Martinis M, Franceschi C, Monti D et al. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 2005; 579:2035–2039.PubMedCrossRefGoogle Scholar
  20. 20.
    Larbi A, Dupuis G, Khalil A et al. Differential role of lipid rafts in the functions of CD4+ and CD8+ human T-lymphocytes with aging. Cell Signal 2006; 18:1017–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Kabouridis PS. Lipid rafts in T-cell receptor signalling. Mol Membr Biol 2006; 23:49–57.PubMedCrossRefGoogle Scholar
  22. 22.
    Matsumoto R, Wang D, Blonska M et al. Phosphorylation of CARMA1 plays a critical role in T-Cell receptor-mediated NF-kappaB activation. Immunity 2005; 23:575–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Fulop T, Larbi A, Douziech N et al. Cytokine receptor signalling and aging. Mech Ageing Dev 2006; 127:526–37.PubMedCrossRefGoogle Scholar
  24. 24.
    Rivnay B, Bergman S, Shinitzky M et al. Correlations between membrane viscosity, serum cholesterol, lymphocyte activation and aging in man. Mech Ageing Dev 1980; 12:119–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Gombos I, Kiss E, Detre C et al. Cholesterol and sphingolipids as lipid organizers of the immune cells’ plasma membrane: their impact on the functions of MHC molecules, effector T-lymphocytes and T-cell death. Immunol Lett 2006; 104:59–69.PubMedCrossRefGoogle Scholar
  26. 26.
    Laude AJ, Prior IA. Plasma membrane microdomains: organization, function and trafficking. Mol Membr Biol 2004; 21:193–205.PubMedCrossRefGoogle Scholar
  27. 27.
    Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997; 387:569–72.PubMedCrossRefGoogle Scholar
  28. 28.
    Kabouridis PS. lipid rafts in T-cell receptor signalling. Mol Membr Biol 2006; 23:49–57.PubMedCrossRefGoogle Scholar
  29. 29.
    Manes S, Viola A. Lipid rafts in lymphocyte activation and migration. Mol Membr Biol 2006; 23:59–69.PubMedCrossRefGoogle Scholar
  30. 30.
    Douglass AD, Vale RD. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T-cells. Cell 2005; 121:937–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Cemerski S, Shaw A. Immune synapses in T-cell activation. Curr Opin Immunol 2006; 18:298–304.PubMedCrossRefGoogle Scholar
  32. 32.
    Larbi A, Douziech N, Dupuis G et al. Age-associated alterations in the recruitment of signal transduction proteins to lipid rafts in human T-lymphocytes. J Leuk Biol 2004; 75:373–381.CrossRefGoogle Scholar
  33. 33.
    Hundt M, Tabata H, Jeon MS et al. Impaired activation and localization of LAT in anergic T-cells as a consequence of a selective palmitoylation defect. Immunity 2006; 24:513–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Hermiston ML, Xu Z, Majeti R et al. Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. J Clin Invest 2002; 109:9–14.PubMedGoogle Scholar
  35. 35.
    Fortin CF, Larbi A, Lesur O et al. Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol 2006; 79:1061–72.PubMedCrossRefGoogle Scholar
  36. 36.
    Pawelec G, Rehbein A, Haehnel K et al. Human T-cell clones in long-term culture as a model of immunosenescence. Immunol Rev 1997; 160:31–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Pawelec G, Mariaini M, Barnett R et al. Human T-cell clones in long-term culture as models for the impact of chronic antigenic stress In: Conn M ed. Handbook of Models for human aging. In: Elsevier, 2006: 781–793.Google Scholar
  38. 38.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11:298–300.PubMedGoogle Scholar
  39. 39.
    Lee KS, Kim SR, Park SJ et al. Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice. J Allergy Clin Immunol 2006; 118:120–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Rider DA, Sinclair AJ, Young SP. Oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T-lymphocyte dysfunction in the elderly. Mech Ageing Dev 2003; 124:191–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Chakravarti B, Abraham GN. Effect of age and oxidative stress on tyrosine phosphorylation of ZAP70. Mech Ageing Dev 2002; 123:297–311.PubMedCrossRefGoogle Scholar
  42. 42.
    Ma S, Ochi H, Cui L et al. Hydrogen peroxide induced down-regulation of CD28 expression of Jurkat cells is associated with a change of site alpha-specific nuclear factor binding activity and the activation of caspase-3. Exp Gerontol 2003; 38:1109–18.PubMedCrossRefGoogle Scholar
  43. 43.
    Kim HJ, Nel AE. The role of phase II antioxidant enzymes in protecting memory T-cells from spontaneous apoptosis in young and old mice. The journal of immunology 2005; 175:(5) 2948–2959.PubMedGoogle Scholar
  44. 44.
    Wellen KE, Hotamisligil GS. Inflammation, stress and diabetes. J Clin Invest 2005; 115:1111–1119.PubMedGoogle Scholar
  45. 45.
    Lesourd BM. Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. Am J Clin Nutr 1997; 66:478S–484S.PubMedGoogle Scholar
  46. 46.
    Lesourd BM. Immune response during disease and recovery in the elderly. Proc Nutr Soc 1999; 58:85–98.PubMedCrossRefGoogle Scholar
  47. 47.
    Fulop T, Tessier D, Carpentier A. The metabolic syndrome. Pathol Biol 2006 (in press).Google Scholar
  48. 48.
    Hotamisligil GS, Arner P, Caro JF et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95:2409–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Res 2004; 12:180–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Fantuzzi G. Adipose tissue, adipokines and inflammation. J Allergy Clin Immunol 2005; 115:911–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Zeyda M, Staffler G, Horejsi V et al. LAT displacement from lipid rafts as a molecular mechanism for the inhibition of T-cell signaling by polyunsaturated fatty acids. J Biol Chem 2002; 277:28418–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Stulnig TM, Berger M, Sigmund T et al. Polyunsaturated fatty acids inhibit T-cell signal transduction by modification of detergent-insoluble membrane domains. J Cell Biol 1998; 143:637–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Larbi A, Grenier A, Frisch F et al. Acute in vivo elevation of intravascular triacylglycerol lipolysis impairs peripheral T-cell activation in humans. Am J Clin Nutr 2005; 82:949–56.PubMedGoogle Scholar
  54. 54.
    Rincon M, Rudin E, Barzilai N. The insulin/IGF-1 signaling in mammals and its relevance to human longevity. Exp Gerontol 2005; 40:873–877.PubMedCrossRefGoogle Scholar
  55. 55.
    Laron Z. Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten of prolong longevity? Mech Ageing Dev 2005; 126:305–307.PubMedCrossRefGoogle Scholar
  56. 56.
    Franceschi C, Olivieri F, Marchegiani F et al. Genes involved in immune response/inflammation. IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians 2005; 126:351–361.Google Scholar
  57. 57.
    Bartke A. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol Metab 2006; 17:33–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Diehn M, Alizadeh AA, Rando OJ et al. Genomic expression programs and the integration of the CD28 costimulatory signal in T-cell activation. Proc Natl Acad Sci USA 2002; 99:11796–801.PubMedCrossRefGoogle Scholar
  59. 59.
    Bonnevier JL, Yarke CA, Mueller DL. Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1→S phase transitions at an optimal rate. Eur J Immunol 2006; 36:1583–97.PubMedCrossRefGoogle Scholar
  60. 60.
    Stentz FB, Kitabchi AE. Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species. Biochem Biophys Res Commun 2005; 335:491–5.PubMedGoogle Scholar
  61. 61.
    Stentz FB, Kitabchi AE. De novo emergence of growth factor receptors in activated human CD4+ and CD8+ T-lymphocytes. Metabolism 2004; 53:117–22.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Tamas Fulop
    • 2
  • Graham Pawelec
    • 2
  • Carl Fortin
    • 2
  • Anis Larbi
    • 1
  1. 1.Tübingen Ageing and Tumour Immunology Group Center for Medical ResearchUniversity of Tübingen Medical SchoolTübingenGermany
  2. 2.Research Center on Aging, Immunology Program, Geriatric Division, Faculty of MedicineUniversity of SherbrookeSherbrookeCanada

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