The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease
By Markus F. Neurath, B. Weigmann, S. Finotto, J. Glickman, E. Nieuwenhuis, H. Iijima, A. Mizoguchi, E. Mizoguchi, J. Mudter, P. Galle and 6 more. Journal of Experimental Medicine, 2002
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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)-γ/interleukin (IL)-4 and transforming growth factor (TGF)-β 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-β signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-γ/IL-4 and TGF-β responses and the development of chronic intestinal inflammation in T cell–mediated colitis. Furthermore, TGF-β was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-β 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.
Subfields: Cancer Research, Immunology
View Paper: https://www.semanticscholar.org/paper/60582e82929bc599f09d3ba89ced50737e1d8810
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Citations in the corpus
- The immunological and genetic basis of inflammatory bowel disease (2003, background): “cgi?l=3595">IL-12Rβ2 chain — a characteristic of T H 1 cell”
- Immune adaptations that maintain homeostasis with the intestinal microbiota (2010, background): “Based on the signalling molecules and transcription factors responsible for their differentiation and their signature cytokine”
- T-bet controls regulatory T cell homeostasis and function during type-1 inflammation (2009, background): “and function normally in vivo in experimental models of asthma and coliti”
- Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. (2007, positive): “Demonstration of T-bet expression in human colonic DCs is a novel observation as Tbet expression had only previously been demonstrated in human colonic T cells (Neurath et al., 2002).”
- Decision making in the immune system: The lineage decisions of helper T cells (2002, positive): “cgi?l=7040">TGF-β ) seems to be able to silence transcription of both GATA3 and T-bet”
- The role of Th1/Th2 polarization in mucosal immunity (2002, background): “This finding is also relevant for the mucosal immune system, as T-bet-deficient T cells fail to induce Th1-mediated experimental coliti”
- Late Developmental Plasticity in the T Helper 17 Lineage (2009, positive): “Nevertheless, mice deficient in STAT4 or T-bet, which are dispensable for Th17 development, are resistant to autoimmunity in these models (Bettelli et al., 2004; Chitnis et al., 2001; Neurath et al., 2002), suggesting that these signaling factors might play a Th17-independent role.”