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. 1991 Aug;85(2):198–201. doi: 10.1111/j.1365-2249.1991.tb05704.x

Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C.

M E North 1, A D Webster 1, J Farrant 1
PMCID: PMC1535737  PMID: 1863999

Abstract

DNA synthesis in response to mitogens has been studied in T cells from nine patients with common variable immunodeficiency (CVI) and seven normal individuals. Five out of the nine patients had cells with subnormal responses to the mitogen phytohaemagglutinin (PHA). As PHA-induced responses are largely mediated through activation of Ca(2+)-dependent protein kinase C, we studied whether the defective response was still present on direct activation of protein kinase C. This was done using combinations of concentrations of phorbol 12,13,-dibutyrate and the calcium ionophore ionomycin which induced proliferation in normal T cells. We found that in CVI patients with T cells which had normal responses to PHA, responses to phorbol ester and ionomycin were at the same level as in normal T cells. However, with this treatment, in which the linkage between the membrane receptor and protein kinase C is bypassed, the level of DNA synthesis was still depressed in the patient group whose T cells had subnormal responses to PHA. IL-2 failed to restore the DNA synthesis to normal levels when added with the phorbol ester and ionomycin to T cells from one patient in this group. These data suggest that in a group of CVI patients there are defects in T cell activation pathways at or down-stream of protein kinase C.

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Selected References

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  1. Alexander D. R., Cantrell D. A. Kinases and phosphatases in T-cell activation. Immunol Today. 1989 Jun;10(6):200–205. doi: 10.1016/0167-5699(89)90325-3. [DOI] [PubMed] [Google Scholar]
  2. Cantrell D. A., Collins M. K., Crumpton M. J. Autocrine regulation of T-lymphocyte proliferation: differential induction of IL-2 and IL-2 receptor. Immunology. 1988 Nov;65(3):343–349. [PMC free article] [PubMed] [Google Scholar]
  3. Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol. 1989 Jan;9(1):22–33. doi: 10.1007/BF00917124. [DOI] [PubMed] [Google Scholar]
  4. Farrant J., Newton C. A., North M. E., Weyman C., Brenner M. K. Production of antibody by human B cells under serum-free conditions. J Immunol Methods. 1984 Mar 30;68(1-2):25–34. doi: 10.1016/0022-1759(84)90133-9. [DOI] [PubMed] [Google Scholar]
  5. Ferris D. K., Willette-Brown J., Ortaldo J. R., Farrar W. L. IL-2 regulation of tyrosine kinase activity is mediated through the p70-75 beta-subunit of the IL-2 receptor. J Immunol. 1989 Aug 1;143(3):870–876. [PubMed] [Google Scholar]
  6. Fiedler W., Sykora K. W., Welte K., Kolitz J. E., Cunningham-Rundles C., Holloway K., Miller G. A., Souza L., Mertelsmann R. T-cell activation defect in common variable immunodeficiency: restoration by phorbol myristate acetate (PMA) or allogeneic macrophages. Clin Immunol Immunopathol. 1987 Aug;44(2):206–218. doi: 10.1016/0090-1229(87)90066-3. [DOI] [PubMed] [Google Scholar]
  7. Hirano T., Fujimoto K., Teranishi T., Nishino N., Onoue K., Maeda S., Shimada K. Phorbol ester increases the level of interleukin 2 mRNA in mitogen-stimulated human lymphocytes. J Immunol. 1984 May;132(5):2165–2167. [PubMed] [Google Scholar]
  8. Kruger G., Welte K., Ciobanu N., Cunningham-Rundles C., Ralph P., Venuta S., Feldman S., Koziner B., Wang C. Y., Moore M. A. Interleukin-2 correction of defective in vitro T-cell mitogenesis in patients with common varied immunodeficiency. J Clin Immunol. 1984 Jul;4(4):295–303. doi: 10.1007/BF00915297. [DOI] [PubMed] [Google Scholar]
  9. Kumagai N., Benedict S. H., Mills G. B., Gelfand E. W. Comparison of phorbol ester/calcium ionophore and phytohemagglutinin-induced signaling in human T lymphocytes. Demonstration of interleukin 2-independent transferrin receptor gene expression. J Immunol. 1988 Jan 1;140(1):37–43. [PubMed] [Google Scholar]
  10. Kumagai N., Benedict S. H., Mills G. B., Gelfand E. W. Requirements for the simultaneous presence of phorbol esters and calcium ionophores in the expression of human T lymphocyte proliferation-related genes. J Immunol. 1987 Sep 1;139(5):1393–1399. [PubMed] [Google Scholar]
  11. López-Botet M., Fontán G., Garcia Rodriguez M. C., de Landázuri M. O. Relationship between IL 2 synthesis and the proliferative response to PHA in different primary immunodeficiencies. J Immunol. 1982 Feb;128(2):679–683. [PubMed] [Google Scholar]
  12. Mills G. B., Girard P., Grinstein S., Gelfand E. W. Interleukin-2 induces proliferation of T lymphocyte mutants lacking protein kinase C. Cell. 1988 Oct 7;55(1):91–100. doi: 10.1016/0092-8674(88)90012-8. [DOI] [PubMed] [Google Scholar]
  13. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  14. North M. E., Spickett G. P., Allsop J., Webster A. D., Farrant J. Defective DNA synthesis by T cells in acquired 'common-variable' hypogammaglobulinaemia on stimulation with mitogens. Clin Exp Immunol. 1989 Apr;76(1):19–23. [PMC free article] [PubMed] [Google Scholar]
  15. North M. E., Webster A. D., Farrant J. Role of interleukin-2 and interleukin-6 in the mitogen responsiveness of T cells from patients with 'common-variable' hypogammaglobulinaemia. Clin Exp Immunol. 1990 Sep;81(3):412–416. doi: 10.1111/j.1365-2249.1990.tb05348.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pastorelli G., Roncarolo M. G., Touraine J. L., Peronne G., Tovo P. A., de Vries J. E. Peripheral blood lymphocytes of patients with common variable immunodeficiency (CVI) produce reduced levels of interleukin-4, interleukin-2 and interferon-gamma, but proliferate normally upon activation by mitogens. Clin Exp Immunol. 1989 Dec;78(3):334–340. [PMC free article] [PubMed] [Google Scholar]
  17. Saltzman E. M., White K., Casnellie J. E. Stimulation of the antigen and interleukin-2 receptors on T lymphocytes activates distinct tyrosine protein kinases. J Biol Chem. 1990 Jun 15;265(17):10138–10142. [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. Valge V. E., Wong J. G., Datlof B. M., Sinskey A. J., Rao A. Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells. Cell. 1988 Oct 7;55(1):101–112. doi: 10.1016/0092-8674(88)90013-x. [DOI] [PubMed] [Google Scholar]

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