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

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RESEARCH PRODUCT

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

Frank Autschbach Jonas Mudter Brandon M. Sullivan Hideki Iijima Laurie H. Glimcher Susetta Finotto Atsushi Mizoguchi Peter R. Galle Benno Weigmann Richard S. Blumberg Edward E. S. Nieuwenhuis Atul K. Bhan Jonathan N. Glickman Emiko Mizoguchi Susanne J. Szabo Markus F. Neurath

subject

CD4-Positive T-Lymphocytes Male colitis Genes RAG-1 T-Lymphocytes medicine.medical_treatment Mice SCID GATA-3 Polymerase Chain Reaction Mice Interleukin 21 0302 clinical medicine Crohn Disease T-Lymphocyte Subsets Immunology and Allergy Cytotoxic T cell IL-2 receptor IFN-γ Mice Inbred BALB C 0303 health sciences Gene Transfer Techniques hemic and immune systems T-Lymphocytes Helper-Inducer Middle Aged 3. Good health Cytokine medicine.anatomical_structure Female Adult T cell Immunology chemical and pharmacologic phenomena Biology T-bet Article TCIRG1 03 medical and health sciences medicine Animals Humans Colitis Immunity Mucosal Interleukin 4 DNA Primers 030304 developmental biology Homeodomain Proteins Base Sequence medicine.disease cytokines Disease Models Animal Gene Expression Regulation Immunology T-Box Domain Proteins Spleen Transcription Factors 030215 immunology

description

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)-beta 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-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta 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.

year	journal	country	edition	language
2002-05-08	Journal of Experimental Medicine

https://doi.org/10.1084/jem.20011956