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. 1993 Nov 1;178(5):1655–1663. doi: 10.1084/jem.178.5.1655

Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells

PMCID: PMC2191249  PMID: 8228812

Abstract

An increased ratio of T helper type 2 (Th2)- vs Th1-like cells contributes to the immune dysregulation in allergic disease situations and in many chronic infections, including AIDS. Th2-type immune responses are characterized by Th cells that produce increased levels of interleukin-4 (IL-4) and decreased levels of interferon gamma (IFN- gamma). The induction of either a Th1- or a Th2-like phenotype may be critically controlled by the antigen-presenting cells and their cytokines, e.g., IFN-alpha. In this study we have determined the frequencies of potential IL-4- and/or IFN-gamma-producing T cells in the peripheral blood of randomly selected healthy individuals, and analyzed whether IFN-alpha controls IL-4 and/or IFN-gamma production. Purified CD4+ or CD8+ T cells were stimulated for 24 h via the T cell receptor/CD3 complex in the presence or absence of IFN-alpha, and single IL-4- and IFN-gamma-secreting cells were detected in enzyme- linked immunospot assays. In the absence of IFN-alpha, CD4 cells produced IFN-gamma at frequencies of 1:50-300, and produced IL-4 at frequencies of 1:110-<1:100,000. Addition of IFN-alpha during the activation of CD4 cells increased the levels of IFN-gamma mRNA. As a consequence, the numbers of IFN-gamma-producing CD4 cells and the amounts of secreted IFN-gamma increased 10-fold. In contrast, IFN-alpha did not increase the frequency of IL-4-secreting CD4 cells. In the absence of IFN-alpha, addition of exogenous IL-4 to cultures of CD4 cells suppressed IFN-gamma secretion by 70%. However, in the presence of IFN-alpha, IL-4 did not display any suppressive effect. Compared with CD4 cells, CD8 cells produced IFN-gamma more frequently (1:5-10) but IL-4 less frequently (1:5,300 to < 1:100,000). IFN-alpha did not display any effect on the frequency of either IFN-gamma or IL-4 production by CD8 cells. Taken together the results indicate that IFN- alpha increases the frequency of IFN-gamma-secreting CD4 Th cells and antagonizes the suppressive effect of IL-4 on IFN-gamma production. As a consequence, IFN-alpha may favor the induction and maintenance of Th1- like cells and thereby counteract Th2-driven allergic immune responses.

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Selected References

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  1. Andersson U., Andersson J., Lindfors A., Wagner K., Möller G., Heusser C. H. Simultaneous production of interleukin 2, interleukin 4 and interferon-gamma by activated human blood lymphocytes. Eur J Immunol. 1990 Jul;20(7):1591–1596. doi: 10.1002/eji.1830200727. [DOI] [PubMed] [Google Scholar]
  2. Brinkmann V., Heusser C. H., Baer J., Kilchherr E., Erard F. Interferon-alpha suppresses the capacity of T cells to help antibody production by human B cells. J Interferon Res. 1992 Aug;12(4):267–274. doi: 10.1089/jir.1992.12.267. [DOI] [PubMed] [Google Scholar]
  3. Brinkmann V., Müller S., Heusser C. H. T cell dependent differentiation of human B cells: direct switch from IgM to IgE, and sequential switch from IgM via IgG to IgA production. Mol Immunol. 1992 Oct;29(10):1159–1164. doi: 10.1016/0161-5890(92)90051-x. [DOI] [PubMed] [Google Scholar]
  4. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  5. Carballido J. M., Carballido-Perrig N., Terres G., Heusser C. H., Blaser K. Bee venom phospholipase A2-specific T cell clones from human allergic and non-allergic individuals: cytokine patterns change in response to the antigen concentration. Eur J Immunol. 1992 Jun;22(6):1357–1363. doi: 10.1002/eji.1830220605. [DOI] [PubMed] [Google Scholar]
  6. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  7. Coffman R. L., Seymour B. W., Lebman D. A., Hiraki D. D., Christiansen J. A., Shrader B., Cherwinski H. M., Savelkoul H. F., Finkelman F. D., Bond M. W. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol Rev. 1988 Feb;102:5–28. doi: 10.1111/j.1600-065x.1988.tb00739.x. [DOI] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  9. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  10. Finkelman F. D., Svetic A., Gresser I., Snapper C., Holmes J., Trotta P. P., Katona I. M., Gause W. C. Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice. J Exp Med. 1991 Nov 1;174(5):1179–1188. doi: 10.1084/jem.174.5.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Francis M. L., Meltzer M. S., Gendelman H. E. Interferons in the persistence, pathogenesis, and treatment of HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):199–207. doi: 10.1089/aid.1992.8.199. [DOI] [PubMed] [Google Scholar]
  12. Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
  13. Gutterman J. U., Fine S., Quesada J., Horning S. J., Levine J. F., Alexanian R., Bernhardt L., Kramer M., Spiegel H., Colburn W. Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med. 1982 May;96(5):549–556. doi: 10.7326/0003-4819-96-5-549. [DOI] [PubMed] [Google Scholar]
  14. Mosmann T. R. Cytokine secretion patterns and cross-regulation of T cell subsets. Immunol Res. 1991;10(3-4):183–188. doi: 10.1007/BF02919690. [DOI] [PubMed] [Google Scholar]
  15. Parronchi P., De Carli M., Manetti R., Simonelli C., Sampognaro S., Piccinni M. P., Macchia D., Maggi E., Del Prete G., Romagnani S. IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol. 1992 Nov 1;149(9):2977–2983. [PubMed] [Google Scholar]
  16. Peleman R., Wu J., Fargeas C., Delespesse G. Recombinant interleukin 4 suppresses the production of interferon gamma by human mononuclear cells. J Exp Med. 1989 Nov 1;170(5):1751–1756. doi: 10.1084/jem.170.5.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pène J., Rousset F., Brière F., Chrétien I., Paliard X., Banchereau J., Spits H., De Vries J. E. IgE production by normal human B cells induced by alloreactive T cell clones is mediated by IL-4 and suppressed by IFN-gamma. J Immunol. 1988 Aug 15;141(4):1218–1224. [PubMed] [Google Scholar]
  19. Recht M., Borden E. C., Knight E., Jr A human 15-kDa IFN-induced protein induces the secretion of IFN-gamma. J Immunol. 1991 Oct 15;147(8):2617–2623. [PubMed] [Google Scholar]
  20. Sedgwick J. D., Holt P. G. A solid-phase immunoenzymatic technique for the enumeration of specific antibody-secreting cells. J Immunol Methods. 1983 Feb 25;57(1-3):301–309. doi: 10.1016/0022-1759(83)90091-1. [DOI] [PubMed] [Google Scholar]
  21. Swain S. L. Regulation of the development of helper T cell subsets. Immunol Res. 1991;10(3-4):177–182. doi: 10.1007/BF02919689. [DOI] [PubMed] [Google Scholar]
  22. van Kimmenade A., Bond M. W., Schumacher J. H., Laquoi C., Kastelein R. A. Expression, renaturation and purification of recombinant human interleukin 4 from Escherichia coli. Eur J Biochem. 1988 Apr 5;173(1):109–114. doi: 10.1111/j.1432-1033.1988.tb13973.x. [DOI] [PubMed] [Google Scholar]

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