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Journal of Biomedical Science

, Volume 6, Issue 4, pp 269–276 | Cite as

Modulation of cytokine responses of murine CD8+ αβ intestinal intraepithelial lymphocytes by IL-4 and IL-12

  • Valentina Gelfanova
  • Yein-Gei Lai
  • Vasily Gelfanov
  • Shiey-Cheng Tzou
  • Yi-Fang Tu
  • Nan-Shih Liao
Original Paper
  • 12 Downloads

Abstract

The immune responses of the intestine mucosa feature the noninflammatory type, such as IgA production and oral tolerance. Th2 type cytokines have been implicated in the induction of these noninflammatory responses. In the present study, cytokine responses of CD8+ and CD4+ TCRαβ+ intestinal intraepithelial lymphocyte (αβ iIEL) subsets to TCR stimulation under the influence of IL-12, IL-4, or CD28 costimulation were examined. IL-12 enhanced production of IL-10 and IFN-γ by the CD8αβ+ αβ iIEL significantly but only marginally affected the CD8αα+ subset, whereas IL-4 induced IL-4, IL-5, and IL-10 production and augmented TGF-β production by both subsets. CD28 costimulation induced production of Th2 cytokines by CD4+ iIEL in the absence of exogenous IL-4. Unlike lymph node CD4+ cells, the CD28 costimulation-induced Th2 differentiation of CD4+ iIEL was not inhibited by IFN-γ. These results demonstrate active cytokine production by CD4+, CD8αβ+, as well as CD8αα+ αβ iIEL. The Th2-skewed cytokine profile of CD8αα+ αβ iIEL and the IFN-γ-resistance of Th2 differentiation of the CD4+ αβ iIEL suggest that both iIEL subsets contribute to the induction of noninflammatory mucosal immune responses.

Key Words

Intestinal intraepithelial lymphocytes Cytokine Th2 responses 

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References

  1. 1.
    Abreu-Martin MT, Targan SR. Regulation of immune responses of the intestinal mucosa. Crit Rev Immunol 16:277–309;1996.PubMedGoogle Scholar
  2. 2.
    Barrett TA, Gajewski TF, Danielpour D, Chang EB, Beagley KW, Bluestone JA. Differential function of intestinal intraepithelial lymphocyte subsets. J Immunol 149;1124–1130;1992.PubMedGoogle Scholar
  3. 3.
    Buzoni-Gatel D, Lepage AC, Dimier-Poisson IH, Bout DT, Kasper LH. Adoptive transfer of gut intraepithelial lymphocytes protects against murine infection withToxoplasma gondii. J Immunol 158:5883–5889;1997.PubMedGoogle Scholar
  4. 4.
    Chen Y, Inobe J-I, Kuchroo VK, Baron JL, Janeway JCA, Weiner HL. Oral tolerance in myelin basic protein T-cell receptor transgenic mice: Suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci USA 93:388–391;1996.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen Y, Kuchroo VK, Inobe J-I, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: Suppression of autoimmune encephalomyelitis. Science 265:1237–1240;1994.Google Scholar
  6. 6.
    Coffman RL, Lebman DA, Shrader B. Transforming growth factor β specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 170:1039–1044;1989.CrossRefPubMedGoogle Scholar
  7. 7.
    Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med 182:1169–1174;1995.CrossRefPubMedGoogle Scholar
  8. 8.
    Croft M, Carter L, Swain SL, Dutton WR. Generation of polarized antigen-specific CD8 effector populations: Reciprocal action of IL-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med 180:1715–1728;1994.CrossRefPubMedGoogle Scholar
  9. 9.
    Dimier IH, Bout DT. Rat intestinal epithelial cell line IEC-6 is activated by recombinant interferon-γ to inhibit replication of the coccidianToxoplasma gondii. Eur J Immunol 23:981;1993.PubMedGoogle Scholar
  10. 10.
    Erard F, Wild MT, Garcia-Sanz JA, Le Gros GG. Switch of CD8 T cells to noncytolytic CD8CD4 cells that make TH2 cytokines and help B cells. Science 260:1802–1805;1993.PubMedGoogle Scholar
  11. 11.
    Fujihashi K, Taguchi T, Aicher WK, McGhee JR, Bluestone JA, Eldridge JH, Kiyono H. Immunoregulatory functions for murine intraepithelial lymphocytes: γ/δ TCR+ cells abrogate oral tolerance, while α/β TCR+ T cells provide B cell help. J Exp Med 175;695–707;1992.CrossRefPubMedGoogle Scholar
  12. 12.
    Fujihashi K, Yamamoto M, McGhee JR, Beagley KW, Kiyono H. Function of αβ TCR+ intestinal intraepithelial lymphocytes: Th1- and Th2-type cytokine production by CD4+CD8- and CD4+CD8+ T cells for helper activity. Int Immunol 5:1473;1993.PubMedGoogle Scholar
  13. 13.
    Gelfanov V, Gelfanova V, Lai Y-G, Liao N-S. Activated αβ-CD8+, but not αα-CD8+, αβ-TCR+ murine intestinal intraepithelial lymphocytes can mediate perforin-based cytotoxicity while both subsets are active in Fas-based cytotoxicity. J Immunol 156:35–41;1996.PubMedGoogle Scholar
  14. 14.
    Gelfanov V, Lai Y-G, Gelfanova V, Dong J-Y, Su J-P, Liao N-S. Differential requirement of CD28 costimulation for activation of murine CD8+ intestinal intraepithelial lymphocyte subsets and lymph node cells. J Immunol 155:76–82;1995.PubMedGoogle Scholar
  15. 15.
    Goodman T, Lefrançois L. Intraepithelial lymphocytes. Anatomical sites, not T cell receptor form, dictates phenotype and function. J Exp Med 170;1569–1581;1989.CrossRefPubMedGoogle Scholar
  16. 16.
    Gramzinski RA, Adams E, Gross JA, Goodman TG, Allison JP, Lefrançois L. T cell receptor-triggered activation of intraepithelial lymphocyte in vitro. Int Immunol 5:145–153;1993.PubMedGoogle Scholar
  17. 17.
    Gross JA, Callas E, Allison JP. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol 149:380–388;1992.PubMedGoogle Scholar
  18. 18.
    Guy-Grand D, Cerf-Bensussan N, Malissen B, Malassis-Seris M, Briottet C, Vassalli P. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: A role for the gut epithelium in T cell differentiation. J Exp Med 173:471–481;1991.CrossRefPubMedGoogle Scholar
  19. 19.
    Guy-Grand D, DiSanto JP, Henchoz P, Malassis-Seris M, Vassalli P. Small bowel enteropathy: Role of intraepithelial lymphocytes and cytokines (IL-12, IFN-γ, TNF) in the induction of epithelial cell death and renewal. Eur J Immunol 28:730–744;1998.CrossRefPubMedGoogle Scholar
  20. 20.
    Guy-Grand D, Rocha B, Mintz P, Malassis-Seris M, Selz F, Malissen B, Vassalli P. Different use of T cell receptor transducing modules in two populations of gut intraepithelial lymphocytes are related to distinct pathways of T cell differentiation. J Exp Med 180:673–679;1994.CrossRefPubMedGoogle Scholar
  21. 21.
    Kaiserlian D, Vidal K, Revillard JP. Murine enterocytes can present soluble antigen to specific class II restricted CD4+ T cells. Eur J Immunol 19:1513;1989.PubMedGoogle Scholar
  22. 22.
    Kjerrulf M, Grdic D, Ekman L, Schon K, Vajdy M, Lycke NY. Interferon-γ receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance. Immunology 92:60–68;1997.CrossRefPubMedGoogle Scholar
  23. 23.
    Kohyama M, Hachimura S, Nanno M, Ishikawa H, Kaminogawa S. Analysis of cytokine producing activity of intestinal intraepithelial T cells from TCR β-chain and δ-chain mutant mice. Microbiol Immunol 41:353–359;1997.PubMedGoogle Scholar
  24. 24.
    Kubo RB, Kappler JW, Marrack P, Pigeon M. Characterization of a monoclonal antibody which detects all murine αβ T cell receptors. J Immunol 142:2736–2742;1989.PubMedGoogle Scholar
  25. 25.
    Kulkarni AB, Huh C-G, Becker D, Geiser A, Lyght M, Flanders KC, Robers AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774;1993.PubMedGoogle Scholar
  26. 26.
    Ledbetter J, Rouse R, Micklem S, Herzenberg L. T cell subsets definded by expression of Ly 1, 2, 3 and Thy-1 antigens. J Exp Med 152:280–295;1980.CrossRefPubMedGoogle Scholar
  27. 27.
    Lefrancois L, Puddington L. Extrathymic intestinal T-cell development: virtual reality? Immunol Today 16:16–21;1995.CrossRefPubMedGoogle Scholar
  28. 28.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-β. Annu Rev Immunol 16:137–161;1998.CrossRefPubMedGoogle Scholar
  29. 29.
    Lu P, Zhou X, Chen S-J, Moorman M, Morris SC, Finkelman FD, Linsley P, Urban JF, Gause WC. CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite. J Exp Med 180:693–698;1994.CrossRefPubMedGoogle Scholar
  30. 30.
    Mayer L, Eisenhardt D, Salomon P, Bauer W, Plous R, Piccinini L. Expression of class II molecules on intestinal epithelial cells in human. Differences between normal and inflammatory bowel disease. Gastroenterology 100:3;1991.PubMedGoogle Scholar
  31. 31.
    Natesan M, Razi-Wolf Z, Reiser H. Costimulation of IL-4 production by murine B7-1 and B7-2 molecules. J Immunol 156:2783–2791;1996.PubMedGoogle Scholar
  32. 32.
    Neurath MF, Fuss I, Kelsall BL, Presky DH, Waegell W, Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-β-mediated oral tolerance. J Exp Med 183:2605–2616;1996.CrossRefPubMedGoogle Scholar
  33. 33.
    Phillips JO, Everson MP, Moldoveanu Z, Lue C, Mestecky J. Synergistic effect of IL-4 and IFN-gamma on the expression of polymeric Ig receptor (secretory component) and IgA binding by human epithelial cells. J Immunol 145:1740–1744;1990.PubMedGoogle Scholar
  34. 34.
    Poussier P, Teh HS, Julius M. Thymus-independent positive and negative selection of T cells expressing a major histocompatibility complex class I restricted transgenic T cell receptor α/β in the intestinal epithelium. J Exp Med 178:1947–1957;1993.CrossRefPubMedGoogle Scholar
  35. 35.
    Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 183:2669–2674;1996.CrossRefPubMedGoogle Scholar
  36. 36.
    Rocha B, Vassalli P, Guy-Grand D. Thymic and extrathymic origins of gut intraepithelial lymphocyte population in mice. J Exp Med 180:681–686;1994.CrossRefPubMedGoogle Scholar
  37. 37.
    Sarmiento M, Glasebrook M, Fitch F. IgG or IgM antibodies reactive to different determinant on the molecular complex bearing Lyt2 antigen block T cell mediated cytolysis in the absence of complement. J Immunol 125:2665–2672;1980.PubMedGoogle Scholar
  38. 38.
    Seder RA, Paul WE, Davis MM, de St Groth BF. 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 176:1091–1098;1992.CrossRefPubMedGoogle Scholar
  39. 39.
    Shull MM, Ormsby I, Kier Ab, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschman T. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359:693–699;1992.PubMedGoogle Scholar
  40. 40.
    Sonoda E, Hitoshi Y, Yamaguchi N. Differential regulation of IgA production by TGF-β and IL-5: TGF-β induces surface IgA-positive cells bearing IL-5 receptor, whereas IL-5 promotes their survival and maturation into IgA-secreting cells. Cell Immunol 140:158–172;1992.CrossRefPubMedGoogle Scholar
  41. 41.
    Spitalny G, Havell E. Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med 159:1560–1565;1984.CrossRefPubMedGoogle Scholar
  42. 42.
    Steineger B, Falk P, Lohmuller M, Van der Meide PH. Class II MHC antigens in the rat digestive system. Normal distribution and induced expression after interferon-gamma treatment in vivo. Immunology 68:507;1989.PubMedGoogle Scholar
  43. 43.
    Viney JL, MacDonald TT. Lymphokine secretion and proliferation of intraepithelial lymphocytes from murine small intestine. Immunology 77:19–24;1992.PubMedGoogle Scholar
  44. 44.
    Yamamoto M, Fujihashi K, Amano M, McGhee JR, Beagley KW, Kiyono H. Cytokine synthesis and apoptosis by intestinal intraepithelial lymphocytes: Signaling of high density αβ T cell receptor+ and γδ T cell receptor+ T cells via T cell receptor-CD3 complex result in interferon-γ and interleukine-5 production, while low density T cells undergo DNA fragmentation. Eur J Immunol 24:1301–1306;1994.PubMedGoogle Scholar
  45. 45.
    Yamamoto M, Fujihashi K, Beagley KW, McGhee JR, Kiyono H. Cytokine synthesis by intestinal intraepithelial lymphocytes. Both γ/δ T cell receptor-positive and α/β T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-γ and IL-5. J Immunol 150:106–114;1993.PubMedGoogle Scholar

Copyright information

© National Science Council 1999

Authors and Affiliations

  • Valentina Gelfanova
    • 3
  • Yein-Gei Lai
    • 3
  • Vasily Gelfanov
    • 3
  • Shiey-Cheng Tzou
    • 1
  • Yi-Fang Tu
    • 2
  • Nan-Shih Liao
    • 3
  1. 1.Department of ZoologyNational Taiwan UniversityTaiwan, ROC
  2. 2.Department of MedicineTaipei Medical CollegeTaipeiTaiwan, ROC
  3. 3.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan (ROC)

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