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The Immunosenescence of Cytolytic T Lymphocytes (CTL): Reduction of Pore-Forming Protein and Granzyme Levels

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Cytotoxic Cells: Recognition, Effector Function, Generation, and Methods

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Abstract

The decline in immunologic vigor that accompanies advancing age has been recognized for many years, and immunologic senescence has been the focus of two recent and extensive reviews (Thoman and Weigle, 1989; Miller, 1990). Although all immunologically active cells, including T cells, B cells, macrophages, and natural killer (NK) cells, appear to exhibit age-related alterations in one or more functions, T cells are widely considered to be the most vulnerable to the potentially deleterious effects of aging. Thymic involution, morphological evidence for which can be observed soon after the immune system functionally matures, is thought to be intimately connected with the subsequent decline in T-cell function (Hirokawa et al., 1990). Although evidence suggests that extrathymic T-cell development is also altered with advanced age (Gorczynski and Chang, 1984), the mechanisms are not yet understood.

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References

  1. Asano Y, Komuro T, Kuko M, Sano K, Tada T (1990): Age-related degeneracy of T cell repertoire: Influence of the aged environment on T cell allorecognition. Gerontology 36 (Suppl 1): 3–9

    Article  Google Scholar 

  2. Bach M-A (1979): Influence of aging on T-cell subpopulations involved in the in vitro generation of allogeneic cytotoxicity. Clin Immunol Immunopathol 13: 220–230

    Article  Google Scholar 

  3. Bender BS, Johnson MP, Small PA (1991): Influenza in sensescent mice: Impared cytotoxic T-lymphocyte activity is correlated with prolonged infection. Immunology 72: 514–519

    Google Scholar 

  4. Bloom ET (1991): Functional importance of CD4& and CD8& cells in CTL activity and associated gene expression. Impact on the age-related decline in lytic activity. Eur J Immunol 21: 1013–1017

    Article  Google Scholar 

  5. Bloom ET, Korn EL (1983): Quantification of natural cytotoxicity by human lymphocyte subpopulations isolated by density: Heterogeneity of the effector cells. J Immunol Methods 58: 323–335

    Article  Google Scholar 

  6. Bloom ET, Kubota LF (1989): Effect of IL-2 in vitro on CTL generation in spleen cells of young and old mice: Asialo GM I & cells are required for the apparent restoration of the CTL response. Cell Immunol 119: 73–84

    Article  Google Scholar 

  7. Bloom ET, Crim JA, Siegel JP (1989): Evaluation of influenza A virus-specific cell mediated immune responses in the elderly. Clin Res 37: 406A

    Google Scholar 

  8. Bloom ET, Kubota LF, Kawakami K (1988): Age-related decline in the lethal hit but not the binding stage of cytotoxic T-cell activity in mice. Cell Immunol 114: 440–446

    Article  Google Scholar 

  9. Bloom ET, Umehara, H, Bleackley RC, Okumura K, Mostowski H, Babbit JT (1990): Age-related decrement in CTL activity is associated with decreased levels of mRNA encoded by two CTL-associated serine esterase genes and the perform gene in mice. Eur J Immunol 20: 2309–2316

    Article  Google Scholar 

  10. Bubeník J, Cinader B, Indrovâ M, Koh SW, Chou C-T (1987): Lymphokine-activated killer (LAK) cells: I. Age-dependent decline of LAK cell-mediated cytotoxicity. Immunol Leu 16: 113–119

    Article  Google Scholar 

  11. Chang M-P, Gorczynski RM (1984): Peripheral (somatic) expansion of the murine cytotoxic T lymphocyte repertoire. I. Analysis of diversity in recognition repertoire of alloreactive T cells derived from the thymus and spleen of adult or aged DBA/2J mice. J Immunol 133: 23752380

    Google Scholar 

  12. Chopra RK, Nagel JE, Chrest FJ, Adler WH (1987): Impaired phorbol ester and calcium ionophore induced proliferation of T cells from old humans. Clin Exp Immunol 70: 456–462

    Google Scholar 

  13. Dunn PL, North RJ (1991): Effect of advanced aging on ability of mice to cause regression of an immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunother 33: 421–423

    Article  Google Scholar 

  14. Effros RB, Walford RL (1983a): Diminished T-cell response to influenza virus in aged mice. Immunology 49: 387–392

    Google Scholar 

  15. Effros RB, Walford RL (1983b): The immune response of aged mice to influenza: Diminished T-cell proliferation, interleukin 2 production and cytotoxicity. Cell Immunol 81: 298–305

    Article  Google Scholar 

  16. Effros RB, Walford RL (1984): The effect of age on the antigen-presenting mechanisms in limiting dilution precursor cell frequency analysis. Cell Immunol 88: 531539

    Google Scholar 

  17. Ernst DN, Hobbs MV, Torbett BE, Glasebrook A, Rehse

    Google Scholar 

  18. E.T. BLOOM AND J.A. HORVATH

    Google Scholar 

  19. MA, Bottomly K, Hayakawa K, Hardy RR, Weigle WO (1990): Differences in the expression profiles of CD45RB, Pgp-1, and 3G11 membrane antigens and in the patterns of lymphokine secretion by splenic CD4& T cells from young and aged mice. J Immunol 145: 1295–1302

    Google Scholar 

  20. Fong TC, Makinodan T (1990): Preferential enhancement by 2-mercaptoethanol of IL-2 responsiveness of T blast cells from old over young mice is associated with potentiated protein kinase C translocation. Immunol Lett 20; 149–154

    Article  Google Scholar 

  21. Goodman SA, Makinodan T (1975): Effect of age on cell-mediated immunity in long-lived mice. Clin Exp Immunol 19: 533–542

    Google Scholar 

  22. Gorczynski RM, Chang M-P (1984): Peripheral (somatic) expansion of the murine cytotoxic T lymphocyte repertoire. II. Comparison of diversity in recognition repertoire of alloreactive T cells in spleen and thymus of young or aged DBA/2J mice transplanted with bone marrow from young or aged donors. J Immunol 133: 2381–2389

    Google Scholar 

  23. Gottesman SRS, Edington J (1990) Proliferative and cytotoxic immune functions in aging mice: V. Deficiency in generation of cytotoxic cells with normal lytic function per cell as demonstrated by the single cell conjugation assay. Aging: Immunol Infec Dis 2: 19–29

    Google Scholar 

  24. Gottesman SRS, Edington JM, Thorbecke GJ (1988): Proliferation and cytotoxic immune functions in aging mice. IV. Effects of suppressor cell populations from aged and young mice. J Immunol 140: 1783–1790

    Google Scholar 

  25. Gottesman SRS, Walford RL, Thorbecke GJ (1984): Proliferative and cytotoxic immune functions in aging. II. Decreased generation of specific suppressor cells in alloreactive cultures. J Immunol 133: 1782–1787

    Google Scholar 

  26. Gottesman SRS, Walford RL, Thorbecke GJ (1985): Proliferative and cytotoxic immune functions in aging mice. III. Exogenous interleukin-2 rich supernatnat only partially restores alloreactivity in vitro. Mech Ageing Dey 31: 103–113

    Article  Google Scholar 

  27. Grossmann A, Maggio-Price L, Jinneman JC, Rabinovitch PS (1991): Influence of aging on intracellular free calcium and proliferation of mouse T-cell subsets from various lymphoid organs. Cell Immunol 135: 118131

    Google Scholar 

  28. Helfrich BA, Segre M, Segre D (1989): Age-related changes in the degeneracy of the mouse T-cell repertoire. Cell Immunol 118: 1–9

    Article  Google Scholar 

  29. Henkart PA (1985): Mechanisms of lymphocyte-mediated cytotoxicity. Annu Rev Immunol 3: 31–58

    Article  Google Scholar 

  30. Hirano T, Nordin AA (1976): Age-associated decline in the in vitro development of cytotoxic lymphocytes in NZB mice. J Immunol 117: 1093–1098

    Google Scholar 

  31. Hirokawa K, Utsuyama M, Kasai M (1990): Role of the thymus in aging of the immune system. In: Biomedical Advances in Aging, Goldstein AL, ed. New York, Plenum, pp. 375–384

    Chapter  Google Scholar 

  32. Ho S-P, Kramer KE, Ershler WB (1990): Effect of host age upon interleukin-2-mediated anti-tumor responses in a murine fibrosarcoma model. Cancer Immunol Immunother 31: 146–150

    Article  Google Scholar 

  33. Jenski LJ (1990): Accessory molecules and antigen requirements for young and aging cytotoxic lymphocytes. Mech Aging Dey 55: 107–122

    Article  Google Scholar 

  34. Kawakami K, Bloom ET (1987): Lymphokine-activated killer cells and aging in mice: Significance for defining the precursor cell. Mech Ageing Dev 41: 229–240

    Article  Google Scholar 

  35. Kawakami K, Bloom ET (1988): Lymphokine-activated killer cells derived from murine bone marrow: Age-associated difference in precursor cell populations demonstrated by response to interferon. Cell Immunol 116: 163–171

    Article  Google Scholar 

  36. Kawasaki A, Shinkai Y, Kuwana Y, Furuya A, Iigo Y, Itoh S, Yagita H, Okumura K (1990): Perforin, a pore-forming protein detectable by monoclonal antibodies, is a functional marker for killer cells. Int Immunol 2: 677–684

    Article  Google Scholar 

  37. Kishimoto S, Shigemoto S, Yamamura Y (1973): Immune response in aged mice. Change of cell-mediated immunity with aging. Transplantation 15: 455–459

    Article  Google Scholar 

  38. Kolber MA, Henkart PA (1988): Quantitation of secretion by rat basophilic leukemia cells by measurements of quinacrine uptake. BBA 939: 459–466

    Article  Google Scholar 

  39. Komuro T, Sano K, Asano Y, Tada T (1990): Analysis of age-related degeneracy of T-cell repertoire—localized functional failure in CD8& T-cells. Scand J Immunol 32: 545–553

    Article  Google Scholar 

  40. Kruisbeek AM, Steinmeier FA (1980): Alloreactive cytotoxic T lymphocytes from aged mice express increased lysis of autologous and third-party target cells. J Immunol 125: 858–864

    Google Scholar 

  41. Menon M, Jaroslow BN, Koesterer R (1974): The decline of cell-mediated immunity in aging mice. J Gerontol 29: 499–505

    Google Scholar 

  42. Miller RA (1984): Age associated decline inprecursor frequency for different T cell-mediated reactions, with preservation of helper or cytotoxic effect per precursor cell. J Immunol 132: 63–68

    Google Scholar 

  43. Miller RA (1990): Aging and the immune response. In: Handbook of the Biology of Aging, Schneider EL, Rowe JW, eds. San Diego: Academic Press, pp. 157–180

    Google Scholar 

  44. Miller RA, Jacobson B, Weil G, Simons ER (1987): Diminished calcium influx in lectin-stimulated T cells from old mice. J Cell Physiol 132: 337–342

    Article  Google Scholar 

  45. Miller RA, Philosophe B, Ginis I, Weil G, Jacobson B (1989): Defective control of cytoplasmic calcium concentration in T lymphocytes from old mice. J Cell Physiol 138: 175–182

    Article  Google Scholar 

  46. Miller RA, Stutman 0 (1981): Decline in aging mice, of the anti-2,4,6-trinitrophenyl (TNP) cytotoxic T cell response attributable to loss of Lyt 2-, interleukin 2-producing helper cell function. Eur J Immunol 11: 751–756

    Google Scholar 

  47. Nagelkerken L, Hertogh-Huijbregts A, Dobber R, Dräger A (1991): Age-related changes in lymphokine production related to a decreased number of CD45RBh’ CD4& T cells. Eur J Immunol 21: 273–281

    Article  Google Scholar 

  48. Nordin AA, Collins GD (1983): Limiting dilution analysis of alloreactive cytotoxic precursor cells in aging mice. J Immunol 131: 2215–2218

    Google Scholar 

  49. Ojcius DM, Zheng LM, Sphicas EC, Zychlinsky A, Young JD-E (1991): Subcellular localization of perforin and serine esterase in lymphokine-activated killer cells and cytotoxic T cells by immunogold labeling. J Immunol 146: 4427–4432

    Google Scholar 

  50. Peters PJ, Borst J, Oorschot V, Fukuda M, Krähenbühl O, Tschopp J, Slot JW, Geuze JH (1991): Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med 173: 1099–1109

    Article  Google Scholar 

  51. Philosophe B, Miller RA (1989): T lymphocyte heterogeneity in old and young mice: Functional defects in T cells selected for poor calcium signal generation. Eur J Immunol 19: 695–699

    Article  Google Scholar 

  52. Philosophe B, Miller RA (1990): Diminished calcium signal generation in subsets of T lymphocytes that predominate in old mice. J Gerontol Biol Sci 45: B87 - B93

    Google Scholar 

  53. Pirruccelo SJ, Collins M, Wilson JE, McManus BM (1989): Age-related changes in naive and memory CD4& T cells in healthy human children. Clin Immunol Immunopathol 52: 341–345

    Article  Google Scholar 

  54. Proust JJ, Filburn CR, Harrison SA, Buchholz MA, Nordin AA (1987): Age-related defect in signal transduction during lectin activation of murine T lymphocytes. J Immunol 139: 1472–1478

    Google Scholar 

  55. Rosenberg AS, Sechler JMG, Horvath JA, Maniero TG, Bloom ET: Assessment of alloreactive T cell sub-populations of aged mice in vivo CD4& but not CD8& T cell mediated responses decline with advanced age. Submitted.

    Google Scholar 

  56. Seth A, Nagarkatti M, Nagarkatti PS, Subbarao B, Udhayakumar V (1990): Macrophages but not B cells from aged mice are defective in stimulating autoreactive T cells in vitro. Mech Ageing Dev 52: 107–124

    Article  Google Scholar 

  57. Sharp A, Kukulansky T, Malkinson Y, Globerson A (1990): The bone marrow as an effector T cell organ in aging. Mech Ageing Dev 52: 219–233

    Article  Google Scholar 

  58. Shigemoto S, Kishimoto S, Yamamura Y (1975): Change

    Google Scholar 

  59. of cell mediated cytotoxicity with aging. J Immunol 115: 307–309

    Google Scholar 

  60. Thoman ML, Weigle WO (1982): Cell-mediated immunity in aged mice: An underlying lesion in IL 2 synthesis. J Immunol 128: 2358–2361

    Google Scholar 

  61. Thoman ML, Weigle WO (1985): Reconstitution of in vivo cell-mediated lympholysis responses in aged mice with interleukin 2. J Immunol 134: 949–952

    Google Scholar 

  62. Thoman ML, Weigle WO (1989): The cellular and subcellular bases of immunosenescence. Adv Immunol 46: 221–261

    Article  Google Scholar 

  63. Tschopp J, Nabholz M (1991): Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol 8: 279–302

    Article  Google Scholar 

  64. Utsuyama M, Hirokawa K (1987): Age-related changes of splenic T cells in mice—A flow cytometric analysis. Mech Ageing Dec 40: 89–102

    Article  Google Scholar 

  65. Wegmann KW, McMaster JS, Green WR (1991): Mechanism of nonresponsiveness to AKR/Gross leukemia virus in AKR.H-2b:Fv-lb mice. An analysis of precursor cytotoxic T lymphocyte frequencies in young versus moderately aged mice. J Immunol 146: 24692477

    Google Scholar 

  66. Weksler ME, Hutteroth TH (1974): Impaired lymphocyte function in aged humans. J Clin Invest 53: 99

    Article  Google Scholar 

  67. Young JD-E, Cohn ZA (1988): How killer cells kill. Sci Am (Jan): 38–44

    Google Scholar 

  68. Young JD-E, Liu C-C, Persechini PM, Cohn ZA (1988): Perforin-dependent and -independent pathways of cytotoxicity mediated by lymphocytes. Immunol Rev 103: 161–202

    Article  Google Scholar 

  69. Zharhary D, Gershon H (1981): Allogeneic T cytotoxic reactivity of senescent mice: Affinity for target cells and determination of cell number. Cell Immunol 60: 470479

    Google Scholar 

  70. Zharhary D, Segev Y, Gershon HE (1984): T-cell cytotoxicity and aging: Differing causes of reduced response in individual mice. Mech Ageing Dev 25: 129140

    Google Scholar 

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Authors
  1. Eda T. Bloom
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  2. Judith A. Horvath
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Editors and Affiliations

  1. Laboratory of Immunology, Biochemistry and Immunopharmacology Unit, NIH-NIAID, 20892, Bethesda, Maryland, USA

    Michail V. Sitkovsky

  2. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 20892, Bethesda, Maryland, USA

    Pierre A. Henkart

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© 1993 Birkhäuser Boston

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Bloom, E.T., Horvath, J.A. (1993). The Immunosenescence of Cytolytic T Lymphocytes (CTL): Reduction of Pore-Forming Protein and Granzyme Levels. In: Sitkovsky, M.V., Henkart, P.A. (eds) Cytotoxic Cells: Recognition, Effector Function, Generation, and Methods. Birkhäuser Boston. https://doi.org/10.1007/978-1-4684-6814-4_38

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  • DOI: https://doi.org/10.1007/978-1-4684-6814-4_38

  • Publisher Name: Birkhäuser Boston

  • Print ISBN: 978-1-4684-6816-8

  • Online ISBN: 978-1-4684-6814-4

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