The Journal of Experimental Medicine
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A correction to this article has been published: J. Exp. Med. 195 (11) 1513
Published 6 May 2002. doi:10.1084/jem.20011956
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© Rockefeller University Press, 0022-1007/2002/5/1129/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 9, May 6, 2002 1129-1143

The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease

M.F. Neurath1,2,3, B. Weigmann1, S. Finotto1, J. Glickman4, E. Nieuwenhuis2, H. Iijima2, A. Mizoguchi4, E. Mizoguchi4, J. Mudter1, P.R. Galle1, A. Bhan4, F. Autschbach5, B.M. Sullivan3, S.J. Szabo3, L.H. Glimcher3 and R.S. Blumberg2

1 Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany
2 Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
3 Harvard School of Public Health and Harvard Medical School, Boston, MA 02115
4 Immunopathology Unit, Massachusetts General Hospital, Boston, MA 02114
5 Institute of Pathology, University of Heidelberg, 49569 Heidelberg, Germany

Address correspondence to Markus F. Neurath, Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Langenbeckstrasse, Germany. Phone: 49-6131-172374; Fax: 49-6131-175508; E-mail: neurath{at}1-med.klinik.uni-mainz.de

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-{gamma}/interleukin (IL)-4 and transforming growth factor (TGF)-ß activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L+ CD4+ T cells exacerbated colitis in reconstituted SCID mice, T-bet–deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet–deficient CD62L- CD4+ T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-ß signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-{gamma}/IL-4 and TGF-ß responses and the development of chronic intestinal inflammation in T cell–mediated colitis. Furthermore, TGF-ß was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-ß and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell–mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.

Key Words: T-bet • GATA-3 • cytokines • colitis • IFN-{gamma}


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