Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Nov 1;180(5):1715–1728. doi: 10.1084/jem.180.5.1715

Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles

PMCID: PMC2191720  PMID: 7525836

Abstract

We have generated primary effector populations from naive CD8 T cells in response to antigen and determined their patterns of cytokine secretion upon restimulation. The effect of exogenous factors on the effector generation was examined and compared with responses of antigen- specific CD4 effectors generated under comparable conditions. CD8 cells from bm1 mice were stimulated with C57BL/6 (B6) antigen presenting cells (APCs) bearing allogeneic class I and CD8 cells from female severe combined immunodeficiency (SCID) B6 mice, transgenic for a T cell receptor alpha/beta (TCR-alpha/beta) that recognizes H-Y on Db, were stimulated with APCs from male mice. In parallel, CD4 cells from bm12 mice were stimulated with alloantigen and CD4 cells from V beta 3/V alpha 11 TCR transgenics were stimulated with a peptide of pigeon cytochrome c on IEk. T cells from both transgenic mice were of naive phenotype whereas normal mice contained 10-20% memory cells. Effector CD8 populations generated were L-selectin low, CD45RB high, and CD44 high. Naive CD8 cells from SCID anti-H-Y mice made little or no cytokine immediately upon stimulation in contrast to naive CD4 which produced large amounts of interleukin 2 (IL-2). Both populations, however, generated primary effectors over 4-5 d that made substantial quantities of many cytokines upon restimulation. Both CD8 and CD4 effectors produced similar patterns of cytokines with alloantigen or specific antigen. Cytokines present during naive CD8 stimulation influenced the cytokine secretion profile of the effectors, as previously shown for CD4 cells, although secretion by CD8 effectors was generally lower than that of CD4 effectors. CD8 cells cultured with IL- 2 alone made predominantly interferon gamma (IFN-gamma) and no IL-4 or IL-5, similar to CD4 cells. Priming with IFN-gamma increased IFN-gamma secretion from CD4 effectors, but had little if any effect on CD8 cells. In contrast, priming with IL-12 generated CD8 effectors, as well as CD4 effectors, producing elevated quantities of IFN-gamma, with similar levels from both the CD4 and CD8 populations. The presence of IL-4 during effector cell generation promoted synthesis of IL-4 and IL- 5 from both CD8 and CD4 cells while downregulating IFN-gamma secretion. CD8 cells made only small amounts of IL-4, more than 100-fold less than CD4 cells, whereas significant levels of IL-5 were induced, only 3-10- fold lower than from CD4.(ABSTRACT TRUNCATED AT 400 WORDS)

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Bradley L. M., Croft M., Swain S. L. T-cell memory: new perspectives. Immunol Today. 1993 May;14(5):197–199. doi: 10.1016/0167-5699(93)90161-D. [DOI] [PubMed] [Google Scholar]
  2. Budd R. C., Cerottini J. C., Horvath C., Bron C., Pedrazzini T., Howe R. C., MacDonald H. R. Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J Immunol. 1987 May 15;138(10):3120–3129. [PubMed] [Google Scholar]
  3. Croft M., Duncan D. D., Swain S. L. Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements. J Exp Med. 1992 Nov 1;176(5):1431–1437. doi: 10.1084/jem.176.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Croft M., Swain S. L. Analysis of CD4+ T cells that provide contact-dependent bystander help to B cells. J Immunol. 1992 Nov 15;149(10):3157–3165. [PubMed] [Google Scholar]
  5. Croft M., Swain S. L. B cell response to T helper cell subsets. II. Both the stage of T cell differentiation and the cytokines secreted determine the extent and nature of helper activity. J Immunol. 1991 Dec 1;147(11):3679–3689. [PubMed] [Google Scholar]
  6. Erard F., Wild M. T., Garcia-Sanz J. A., Le Gros G. Switch of CD8 T cells to noncytolytic CD8-CD4- cells that make TH2 cytokines and help B cells. Science. 1993 Jun 18;260(5115):1802–1805. doi: 10.1126/science.8511588. [DOI] [PubMed] [Google Scholar]
  7. Ernst D. N., Weigle W. O., Noonan D. J., McQuitty D. N., Hobbs M. V. The age-associated increase in IFN-gamma synthesis by mouse CD8+ T cells correlates with shifts in the frequencies of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression. J Immunol. 1993 Jul 15;151(2):575–587. [PubMed] [Google Scholar]
  8. 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]
  9. Fiorentino D. F., Zlotnik A., Vieira P., Mosmann T. R., Howard M., Moore K. W., O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991 May 15;146(10):3444–3451. [PubMed] [Google Scholar]
  10. Gasser D. L., Silvers W. K. Genetics and immunology of sex-linked antigens. Adv Immunol. 1972;15:215–247. doi: 10.1016/s0065-2776(08)60686-0. [DOI] [PubMed] [Google Scholar]
  11. Granger G. A., Williams T. W. Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor. Nature. 1968 Jun 29;218(5148):1253–1254. doi: 10.1038/2181253a0. [DOI] [PubMed] [Google Scholar]
  12. Horvat B., Loukides J. A., Anandan L., Brewer E., Flood P. M. Production of interleukin 2 and interleukin 4 by immune CD4-CD8+ and their role in the generation of antigen-specific cytotoxic T cells. Eur J Immunol. 1991 Aug;21(8):1863–1871. doi: 10.1002/eji.1830210813. [DOI] [PubMed] [Google Scholar]
  13. Hsieh C. S., Heimberger A. B., Gold J. S., O'Garra A., Murphy K. M. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065–6069. doi: 10.1073/pnas.89.13.6065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Kimata H., Yoshida A., Ishioka C., Lindley I., Mikawa H. Interleukin 8 (IL-8) selectively inhibits immunoglobulin E production induced by IL-4 in human B cells. J Exp Med. 1992 Oct 1;176(4):1227–1231. doi: 10.1084/jem.176.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klein J. R., Raulet D. H., Pasternack M. S., Bevan M. J. Cytotoxic T lymphocytes produce immune interferon in response to antigen or mitogen. J Exp Med. 1982 Apr 1;155(4):1198–1203. doi: 10.1084/jem.155.4.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Le Gros G., Ben-Sasson S. Z., Seder R., Finkelman F. D., Paul W. E. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. doi: 10.1084/jem.172.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mehrotra P. T., Wu D., Crim J. A., Mostowski H. S., Siegel J. P. Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. J Immunol. 1993 Sep 1;151(5):2444–2452. [PubMed] [Google Scholar]
  19. Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):421–425. doi: 10.1073/pnas.89.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Morris A. G., Lin Y. L., Askonas B. A. Immune interferon release when a cloned cytotoxic T-cell line meets its correct influenza-infected target cell. Nature. 1982 Jan 14;295(5845):150–152. doi: 10.1038/295150a0. [DOI] [PubMed] [Google Scholar]
  21. Pfeifer J. D., McKenzie D. T., Swain S. L., Dutton R. W. B cell stimulatory factor 1 (interleukin 4) is sufficient for the proliferation and differentiation of lectin-stimulated cytolytic T lymphocyte precursors. J Exp Med. 1987 Nov 1;166(5):1464–1470. doi: 10.1084/jem.166.5.1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  23. Sanderson C. J. Interleukin-5, eosinophils, and disease. Blood. 1992 Jun 15;79(12):3101–3109. [PubMed] [Google Scholar]
  24. Seder R. A., Boulay J. L., Finkelman F., Barbier S., Ben-Sasson S. Z., Le Gros G., Paul W. E. CD8+ T cells can be primed in vitro to produce IL-4. J Immunol. 1992 Mar 15;148(6):1652–1656. [PubMed] [Google Scholar]
  25. 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]
  26. Seder R. A., Paul W. E., Davis M. M., Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992 Oct 1;176(4):1091–1098. doi: 10.1084/jem.176.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sprent J., Schaefer M. Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens. J Exp Med. 1985 Dec 1;162(6):2068–2088. doi: 10.1084/jem.162.6.2068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  29. Swain S. L., Weinberg A. D., English M. CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro. J Immunol. 1990 Mar 1;144(5):1788–1799. [PubMed] [Google Scholar]
  30. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  31. Tanaka T., Hu-Li J., Seder R. A., Fazekas de St Groth B., Paul W. E. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. doi: 10.1073/pnas.90.13.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tonkonogy S. L., McKenzie D. T., Swain S. L. Regulation of isotype production by IL-4 and IL-5. Effects of lymphokines on Ig production depend on the state of activation of the responding B cells. J Immunol. 1989 Jun 15;142(12):4351–4360. [PubMed] [Google Scholar]
  33. Widmer M. B., Grabstein K. H. Regulation of cytolytic T-lymphocyte generation by B-cell stimulatory factor. Nature. 1987 Apr 23;326(6115):795–798. doi: 10.1038/326795a0. [DOI] [PubMed] [Google Scholar]
  34. Wu C. Y., Demeure C., Kiniwa M., Gately M., Delespesse G. IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells. J Immunol. 1993 Aug 15;151(4):1938–1949. [PubMed] [Google Scholar]
  35. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol. 1990;8:531–556. doi: 10.1146/annurev.iy.08.040190.002531. [DOI] [PubMed] [Google Scholar]

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

RESOURCES