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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1987 Nov;70(2):456–462.

Impaired phorbol ester and calcium ionophore induced proliferation of T cells from old humans.

R K Chopra 1, J E Nagel 1, F J Chrest 1, W H Adler 1
PMCID: PMC1542072  PMID: 3123107

Abstract

Current models of T cell activation implicate increases in intracellular free Ca2+ concentration and activation of the Ca2+ and phospholipid dependent enzyme protein kinase C (PKC) as important early events leading to interleukin 2 (IL-2) production, interleukin 2 receptor (IL-2R) expression, and subsequent cell proliferation. The present study examined the age-related defect in T cell proliferation to determine if signals that activate PKC and increase intracytosolic free Ca2+ concentration might be defective. Using phorbol myristate acetate (PMA), which directly activates PKC, and Ca2+ ionophore A23187, which increases intracellular cytoplasmic free Ca2+ concentration, the induction of IL-2 secretion, IL-2R expression and cell proliferation were studied. The results demonstrate that following stimulation with PMA and A23187, purified T cells from elderly subjects demonstrate low levels of IL-2 production, IL-2R expression and cell proliferation. Exogenous purified human IL-2 did not fully correct the low proliferative responses of T cells from old donors, however, did markedly boost the response. While it appears that the inability of T cells to express IL-2R and respond to IL-2, along with a lower endogenous IL-2 production are limiting factors in cell proliferation, the inability of PMA and A23187 to correct this defect suggests that the early phases of signal transduction per se are probably not a primary cause of the immunodeficiency seen in ageing.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berridge M. J. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984 Jun 1;220(2):345–360. doi: 10.1042/bj2200345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chang M. P., Makinodan T., Peterson W. J., Strehler B. L. Role of T cells and adherent cells in age-related decline in murine interleukin 2 production. J Immunol. 1982 Dec;129(6):2426–2430. [PubMed] [Google Scholar]
  3. Doggett D. L., Chang M. P., Makinodan T., Strehler B. L. Cellular and molecular aspects of immune system aging. Mol Cell Biochem. 1981 Jul;37(3):137–156. doi: 10.1007/BF02354883. [DOI] [PubMed] [Google Scholar]
  4. Falkoff R. M., Peters M., Fauci A. S. T cell enrichment and depletion of human peripheral blood mononuclear cell preparations. Unexpected findings in the study of the functional activities of the separated populations. J Immunol Methods. 1982;50(1):39–49. doi: 10.1016/0022-1759(82)90302-7. [DOI] [PubMed] [Google Scholar]
  5. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  6. Gillis S., Kozak R., Durante M., Weksler M. E. Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest. 1981 Apr;67(4):937–942. doi: 10.1172/JCI110143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gilman S. C., Rosenberg J. S., Feldman J. D. T lymphocytes of young and aged rats. II. Functional defects and the role of interleukin-2. J Immunol. 1982 Feb;128(2):644–650. [PubMed] [Google Scholar]
  8. Isakov N., Altman A. Tumor promoters in conjunction with calcium ionophores mimic antigenic stimulation by reactivation of alloantigen-primed murine T lymphocytes. J Immunol. 1985 Dec;135(6):3674–3680. [PubMed] [Google Scholar]
  9. Miller R. A. Immunodeficiency of aging: restorative effects of phorbol ester combined with calcium ionophore. J Immunol. 1986 Aug 1;137(3):805–808. [PubMed] [Google Scholar]
  10. Nagel J. E., Chrest F. J., Adler W. H. Enumeration of T lymphocyte subsets by monoclonal antibodies in young and aged humans. J Immunol. 1981 Nov;127(5):2086–2088. [PubMed] [Google Scholar]
  11. Nagel J. E., Chrest F. J., Adler W. H. Mitogenic activity of 12-O-tetradecanoyl phorbol-13-acetate on peripheral blood lymphocytes from young and aged adults. Clin Exp Immunol. 1982 Jul;49(1):217–224. [PMC free article] [PubMed] [Google Scholar]
  12. Nagel J. E., Chrest F. J., Pyle R. S., Adler W. H. Monoclonal antibody analysis of T-lymphocyte subsets in young and aged adults. Immunol Commun. 1983;12(2):223–237. doi: 10.3109/08820138309066871. [DOI] [PubMed] [Google Scholar]
  13. Niedel J. E., Kuhn L. J., Vandenbark G. R. Phorbol diester receptor copurifies with protein kinase C. Proc Natl Acad Sci U S A. 1983 Jan;80(1):36–40. doi: 10.1073/pnas.80.1.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nishizuka Y. Turnover of inositol phospholipids and signal transduction. Science. 1984 Sep 21;225(4668):1365–1370. doi: 10.1126/science.6147898. [DOI] [PubMed] [Google Scholar]
  15. Schwab R., Hausman P. B., Rinnooy-Kan E., Weksler M. E. Immunological studies of ageing. X. Impaired T lymphocytes and normal monocyte response from elderly humans to the mitogenic antibodies OKT3 and Leu 4. Immunology. 1985 Aug;55(4):677–684. [PMC free article] [PubMed] [Google Scholar]
  16. Smith K. A., Cantrell D. A. Interleukin 2 regulates its own receptors. Proc Natl Acad Sci U S A. 1985 Feb;82(3):864–868. doi: 10.1073/pnas.82.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Thoman M. L., Weigle W. O. Lymphokines and aging: interleukin-2 production and activity in aged animals. J Immunol. 1981 Nov;127(5):2102–2106. [PubMed] [Google Scholar]
  18. Truneh A., Albert F., Golstein P., Schmitt-Verhulst A. M. Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature. 1985 Jan 24;313(6000):318–320. doi: 10.1038/313318a0. [DOI] [PubMed] [Google Scholar]
  19. Tsien R. Y., Pozzan T., Rink T. J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 1982 Jan 7;295(5844):68–71. doi: 10.1038/295068a0. [DOI] [PubMed] [Google Scholar]
  20. Welte K., Andreeff M., Platzer E., Holloway K., Rubin B. Y., Moore M. A., Mertelsmann R. Interleukin 2 regulates the expression of Tac antigen on peripheral blood T lymphocytes. J Exp Med. 1984 Nov 1;160(5):1390–1403. doi: 10.1084/jem.160.5.1390. [DOI] [PMC free article] [PubMed] [Google Scholar]

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