Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Oct 1;182(4):1067–1077. doi: 10.1084/jem.182.4.1067

Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15

PMCID: PMC2192305  PMID: 7561680

Abstract

Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL- 2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN- gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

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

  1. Bowen D. L., Lane H. C., Fauci A. S. Immunopathogenesis of the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Nov;103(5):704–709. doi: 10.7326/0003-4819-103-5-704. [DOI] [PubMed] [Google Scholar]
  2. Carson W. E., Giri J. G., Lindemann M. J., Linett M. L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M. A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. doi: 10.1084/jem.180.4.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciobanu N., Welte K., Kruger G., Venuta S., Gold J., Feldman S. P., Wang C. Y., Koziner B., Moore M. A., Safai B. Defective T-cell response to PHA and mitogenic monoclonal antibodies in male homosexuals with acquired immunodeficiency syndrome and its in vitro correction by interleukin 2. J Clin Immunol. 1983 Oct;3(4):332–340. doi: 10.1007/BF00915794. [DOI] [PubMed] [Google Scholar]
  5. Clerici M., Giorgi J. V., Chou C. C., Gudeman V. K., Zack J. A., Gupta P., Ho H. N., Nishanian P. G., Berzofsky J. A., Shearer G. M. Cell-mediated immune response to human immunodeficiency virus (HIV) type 1 in seronegative homosexual men with recent sexual exposure to HIV-1. J Infect Dis. 1992 Jun;165(6):1012–1019. doi: 10.1093/infdis/165.6.1012. [DOI] [PubMed] [Google Scholar]
  6. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Clerici M., Stocks N. I., Zajac R. A., Boswell R. N., Bernstein D. C., Mann D. L., Shearer G. M., Berzofsky J. A. Interleukin-2 production used to detect antigenic peptide recognition by T-helper lymphocytes from asymptomatic HIV-seropositive individuals. Nature. 1989 Jun 1;339(6223):383–385. doi: 10.1038/339383a0. [DOI] [PubMed] [Google Scholar]
  10. Fahey J. L., Prince H., Weaver M., Groopman J., Visscher B., Schwartz K., Detels R. Quantitative changes in T helper or T suppressor/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders. Am J Med. 1984 Jan;76(1):95–100. doi: 10.1016/0002-9343(84)90756-3. [DOI] [PubMed] [Google Scholar]
  11. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  13. Graziosi C., Pantaleo G., Gantt K. R., Fortin J. P., Demarest J. F., Cohen O. J., Sékaly R. P., Fauci A. S. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248–252. doi: 10.1126/science.8023143. [DOI] [PubMed] [Google Scholar]
  14. Hauser G. J., Bino T., Rosenberg H., Zakuth V., Geller E., Spirer Z. Interleukin-2 production and response to exogenous interleukin-2 in a patient with the acquired immune deficiency syndrome (AIDS). Clin Exp Immunol. 1984 Apr;56(1):14–17. [PMC free article] [PubMed] [Google Scholar]
  15. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  16. Kovacs J. A., Baseler M., Dewar R. J., Vogel S., Davey R. T., Jr, Falloon J., Polis M. A., Walker R. E., Stevens R., Salzman N. P. Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N Engl J Med. 1995 Mar 2;332(9):567–575. doi: 10.1056/NEJM199503023320904. [DOI] [PubMed] [Google Scholar]
  17. Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
  18. Lane H. C., Fauci A. S. Immunologic abnormalities in the acquired immunodeficiency syndrome. Annu Rev Immunol. 1985;3:477–500. doi: 10.1146/annurev.iy.03.040185.002401. [DOI] [PubMed] [Google Scholar]
  19. Lifson J. D., Benike C. J., Mark D. F., Koths K., Engleman E. G. Human recombinant interleukin-2 partly reconstitutes deficient in-vitro immune responses of lymphocytes from patients with AIDS. Lancet. 1984 Mar 31;1(8379):698–702. doi: 10.1016/s0140-6736(84)92220-7. [DOI] [PubMed] [Google Scholar]
  20. Maggi E., Mazzetti M., Ravina A., Annunziato F., de Carli M., Piccinni M. P., Manetti R., Carbonari M., Pesce A. M., del Prete G. Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science. 1994 Jul 8;265(5169):244–248. doi: 10.1126/science.8023142. [DOI] [PubMed] [Google Scholar]
  21. Manetti R., Gerosa F., Giudizi M. G., Biagiotti R., Parronchi P., Piccinni M. P., Sampognaro S., Maggi E., Romagnani S., Trinchieri G. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med. 1994 Apr 1;179(4):1273–1283. doi: 10.1084/jem.179.4.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Morgan D. A., Ruscetti F. W., Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. doi: 10.1126/science.181845. [DOI] [PubMed] [Google Scholar]
  23. Prince H. E., Kermani-Arab V., Fahey J. L. Depressed interleukin 2 receptor expression in acquired immune deficiency and lymphadenopathy syndromes. J Immunol. 1984 Sep;133(3):1313–1317. [PubMed] [Google Scholar]
  24. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Puccetti P., Wolf S. F., Bistoni F. IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis. J Immunol. 1994 Dec 1;153(11):5167–5175. [PubMed] [Google Scholar]
  25. Rosenberg S. A., Lotze M. T., Muul L. M., Leitman S., Chang A. E., Ettinghausen S. E., Matory Y. L., Skibber J. M., Shiloni E., Vetto J. T. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985 Dec 5;313(23):1485–1492. doi: 10.1056/NEJM198512053132327. [DOI] [PubMed] [Google Scholar]
  26. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shearer G. M., Bernstein D. C., Tung K. S., Via C. S., Redfield R., Salahuddin S. Z., Gallo R. C. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986 Oct 15;137(8):2514–2521. [PubMed] [Google Scholar]
  28. Trinchieri G., Scott P. The role of interleukin 12 in the immune response, disease and therapy. Immunol Today. 1994 Oct;15(10):460–463. doi: 10.1016/0167-5699(94)90189-9. [DOI] [PubMed] [Google Scholar]
  29. Tsudo M., Kitamura F., Miyasaka M. Characterization of the interleukin 2 receptor beta chain using three distinct monoclonal antibodies. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1982–1986. doi: 10.1073/pnas.86.6.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wang Z. E., Zheng S., Corry D. B., Dalton D. K., Seder R. A., Reiner S. L., Locksley R. M. Interferon gamma-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12932–12936. doi: 10.1073/pnas.91.26.12932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhou P., Sieve M. C., Bennett J., Kwon-Chung K. J., Tewari R. P., Gazzinelli R. T., Sher A., Seder R. A. IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J Immunol. 1995 Jul 15;155(2):785–795. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES