Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Jun 1;183(6):2669–2674. doi: 10.1084/jem.183.6.2669

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

PMCID: PMC2192626  PMID: 8676088

Abstract

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Barnard J. A., Warwick G. J., Gold L. I. Localization of transforming growth factor beta isoforms in the normal murine small intestine and colon. Gastroenterology. 1993 Jul;105(1):67–73. doi: 10.1016/0016-5085(93)90011-z. [DOI] [PubMed] [Google Scholar]
  2. Chen Y., Kuchroo V. K., Inobe J., Hafler D. A., Weiner H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994 Aug 26;265(5176):1237–1240. doi: 10.1126/science.7520605. [DOI] [PubMed] [Google Scholar]
  3. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  4. Coffman R. L., Varkila K., Scott P., Chatelain R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol Rev. 1991 Oct;123:189–207. doi: 10.1111/j.1600-065x.1991.tb00611.x. [DOI] [PubMed] [Google Scholar]
  5. Dasch J. R., Pace D. R., Waegell W., Inenaga D., Ellingsworth L. Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. J Immunol. 1989 Mar 1;142(5):1536–1541. [PubMed] [Google Scholar]
  6. Fowell D., Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med. 1993 Mar 1;177(3):627–636. doi: 10.1084/jem.177.3.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kuchroo V. K., Das M. P., Brown J. A., Ranger A. M., Zamvil S. S., Sobel R. A., Weiner H. L., Nabavi N., Glimcher L. H. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell. 1995 Mar 10;80(5):707–718. doi: 10.1016/0092-8674(95)90349-6. [DOI] [PubMed] [Google Scholar]
  8. Kulkarni A. B., Huh C. G., Becker D., Geiser A., Lyght M., Flanders K. C., Roberts A. B., Sporn M. B., Ward J. M., Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770–774. doi: 10.1073/pnas.90.2.770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Mombaerts P., Mizoguchi E., Grusby M. J., Glimcher L. H., Bhan A. K., Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell. 1993 Oct 22;75(2):274–282. doi: 10.1016/0092-8674(93)80069-q. [DOI] [PubMed] [Google Scholar]
  12. Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
  13. Morrissey P. J., Charrier K., Braddy S., Liggitt D., Watson J. D. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med. 1993 Jul 1;178(1):237–244. doi: 10.1084/jem.178.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Powrie F., Coffman R. L. Cytokine regulation of T-cell function: potential for therapeutic intervention. Immunol Today. 1993 Jun;14(6):270–274. doi: 10.1016/0167-5699(93)90044-L. [DOI] [PubMed] [Google Scholar]
  15. Powrie F., Correa-Oliveira R., Mauze S., Coffman R. L. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med. 1994 Feb 1;179(2):589–600. doi: 10.1084/jem.179.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Powrie F., Leach M. W., Mauze S., Caddle L. B., Coffman R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993 Nov;5(11):1461–1471. doi: 10.1093/intimm/5.11.1461. [DOI] [PubMed] [Google Scholar]
  17. Powrie F., Leach M. W., Mauze S., Menon S., Caddle L. B., Coffman R. L. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994 Oct;1(7):553–562. doi: 10.1016/1074-7613(94)90045-0. [DOI] [PubMed] [Google Scholar]
  18. Powrie F., Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J Exp Med. 1990 Dec 1;172(6):1701–1708. doi: 10.1084/jem.172.6.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Powrie F. T cells in inflammatory bowel disease: protective and pathogenic roles. Immunity. 1995 Aug;3(2):171–174. doi: 10.1016/1074-7613(95)90086-1. [DOI] [PubMed] [Google Scholar]
  20. Sadlack B., Merz H., Schorle H., Schimpl A., Feller A. C., Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. doi: 10.1016/0092-8674(93)80067-o. [DOI] [PubMed] [Google Scholar]
  21. Sakaguchi S., Fukuma K., Kuribayashi K., Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985 Jan 1;161(1):72–87. doi: 10.1084/jem.161.1.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Saoudi A., Simmonds S., Huitinga I., Mason D. Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells. J Exp Med. 1995 Aug 1;182(2):335–344. doi: 10.1084/jem.182.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sartor R. B. Pathogenetic and clinical relevance of cytokines in inflammatory bowel disease. Immunol Res. 1991;10(3-4):465–471. doi: 10.1007/BF02919743. [DOI] [PubMed] [Google Scholar]
  24. Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
  25. Sher A., Gazzinelli R. T., Oswald I. P., Clerici M., Kullberg M., Pearce E. J., Berzofsky J. A., Mosmann T. R., James S. L., Morse H. C., 3rd Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992 Jun;127:183–204. doi: 10.1111/j.1600-065x.1992.tb01414.x. [DOI] [PubMed] [Google Scholar]
  26. Shull M. M., Ormsby I., Kier A. B., Pawlowski S., Diebold R. J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. doi: 10.1038/359693a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Weiner H. L., Friedman A., Miller A., Khoury S. J., al-Sabbagh A., Santos L., Sayegh M., Nussenblatt R. B., Trentham D. E., Hafler D. A. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol. 1994;12:809–837. doi: 10.1146/annurev.iy.12.040194.004113. [DOI] [PubMed] [Google Scholar]
  28. Windhagen A., Scholz C., Höllsberg P., Fukaura H., Sette A., Hafler D. A. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity. 1995 Apr;2(4):373–380. doi: 10.1016/1074-7613(95)90145-0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES