A Good “Bet” for the Role of CD4+ Lymphocytes in the Pathogenesis of Crohn Disease

The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn Disease. M.F. Neurath, B. Weigmann, S. Finotto, J. Glickman, E. Nieuwenhuis, H. Iijima, A. Mizoguchi, E. Mizoguchi, J. Mudter, P.R. Gallc, A. Bhan, F. Autschbach, B.M. Sullivan, S.J. Szabo, L.H. Glimcher, and R.S. Blumberg J Exp Med 2002;195:1129–43 Summary: Based on recent evidence suggesting that the transcription factor T-bet is a master switch for Th1 polarization, Neurath and colleagues investigated its role in patients with inflammatory bowel disease (IBD) and various animal models of colitis. Accumulation of T-bet was detected in the cytoplasm and nucleus of the intestinal lamina propria T cells of patients with Crohn disease but not in cells from controls as assessed by three complementary techniques. In contrast, expression of the Th2 transcription factor GATA-3 was decreased in intestinal lamina propria T cells of Crohn disease patients relative to controls. In animal studies, the role of T-bet was characterized using established Th1 and Th2 colitis models: T-bet–deficient mice and mice made to overexpress T-bet through viral transfection. First, in TH1 colitis models (adoptive transfer of CD62L+CD4+ cells into SCID or RAG mice, IL-10–deficient mice and TNBS induced colitis), an increase in T-bet transcript and protein expression was seen in T-cell enriched lamina propria cells from the colons of each of the models. In contrast, T-bet expression remained unchanged or was reduced in T-cell enriched lamina propria cells isolated from the colons of mice with Th2-mediated intestinal inflammation (TCRα-/-μ-/- associated colitis and oxazolone-mediated colitis). Second, studies using T-bet–deficient mice confirmed the critical role of T-bet in Th1-mediated intestinal inflammation. The adoptive transfer of CD62L+CD4+ cells from T-bet deficient mice failed to induce colitis in immunodeficient mice (Th1 models of inflammation). Furthermore, T-bet deficient mice showed an enhanced susceptibility to oxazolone-mediated colitis. Finally, adoptive transfer of CD62L+ CD4+ cells retrovirally transfected to overexpress T-bet resulted in earlier and more severe colitis in both RAG and SCID mice. The functional role of T-bet on the cytokine profile of lamina propria lymphocytes in vitro was also assessed. T-cell enriched lamina propria lymphocytes isolated from T-bet–deficient mice produced lower levels of the Th1 cytokine IFN-γ and higher levels of the Th2 cytokines IL-4, IL-6, and IL-10 after costimulation with anti-CD3 and anti-CD28 antibodies than did lymphocytes from control litter mates. In addition, lymphocytes from T-bet deficient mice produced increased amounts of the regulatory cytokine TGF-β. To delineate the signaling pathway between T-bet and TGF-β, the authors investigated the TGF-β regulatory protein Smad 7, an inhibitor of TGF-β. Isolation of TGF-β–producing cells from T-bet deficient mice revealed decreased Smad 7 expression. These results suggest that T-bet is involved in the inhibition of TGF-β signaling through its regulation of Smad 7. Comment: Current evidence suggests that the pathogenesis of IBD involves an interplay between microbes and host immune responses (Scand J Gastroenterol 2001; 234(suppl): 29–40). In particular, emphasis has been placed on the role of T helper cells in mediating mucosal inflammation (Gut 2002; 50(suppl. III):iii60–iii64, Scand J Immumol 2000; 51:2–9). T helper cells can differentiate into one of two distinct subsets: Th1 cells, which are involved in cell-mediated immunity, or Th2 cells, which mediate humoral immunity (Nature Immunol 2002; 3:506–8). Th1 cells are generated after IL-12 stimulation and produce IFN-γ, while Th2 cells are generated after IL-4 stimulation and produce IL-4 and IL-5. In animal models of IBD which resemble Crohn disease, CD4+ lamina propria lymphocytes have a predominantly Th1 phenotype, while lymphocytes in ulcerative colitis models display a Th2 phenotype (J Immunol 1996; 157:1261–70). The study from Neurath and colleagues supports the role of Th1 lymphocytes in the pathogenesis of Crohn disease through alteration in the expression of T-bet. T-bet has been proposed as a master switch for Th1 commitment during activation of naive T cells (Cell 2000; 100:655–669). T-bet is a 62-kd protein with a T box DNA-binding domain which is expressed in CD4+ lymphocytes, as well as in CD8+ lymphocytes and natural killer cells (Science 2002; 295:338–42). In CD4+ lymphocytes, this transcription factor is responsible for two major elements of Th1 differentiation: expression of IFN-γ, the hallmark Th1 cytokine, as well as the induction and maintenance of the IL-12 receptor β2 gene. T-bet is encoded on chromosome 17 (Genomics 2000; 70:41–8) which is not identified as an IBD susceptibility locus. It is speculated to autoregulate its expression through an unknown mechanism (Science 2001; 292:1907–10). However, recent evidence suggests that it regulates its expression through the IFN-γ/STAT1 (Science 2001; 292:1907–1910) and the IL-12/STAT4 pathways (Nature Immunol 2002; 3:549–557, Cell 2000; 100:655–669, Immunol Today 2000; 21:479–483). The STAT1 induction of T-bet is an early event, while STAT4 induction occurs later. This dynamic process is also supported by the fact that naive T cells express IFN-γ receptors but not IL-12 receptor β2 or STAT4. Therefore naive T cells would be ill equipped to induce T-bet initially through the IL-12/STAT4 pathway (Nature Immunol 2002; 3:549–57). T-bet induces IFN-γ production by chromatin remodeling of the IFN-γ gene. In addition, T-bet is responsible for histone acetylation of the IFN-γ gene thereby maintaining the gene in a transcriptionally permissive state (Nature Immunol 2002; 3:652–58, J Immunol 2002; 169:647–650). Furthermore, T-bet enhances expression of the IL-12 receptor β2 on CD4+ T cells promoting signaling through the IL-12 pathway. Neurath and Blumberg also identified an interaction between T-bet and the regulatory cytokine TGF-β. In the gastrointestinal tract, TGF-β as well as IL-10 are considered anti-inflammatory cytokines. TGF-β and T-bet display a reciprocal relationship. TGF-β suppresses T-bet expression (J Exp Med 2002; 195:1499–1505) and T-bet deficiency results in enhanced TGF-β expression. Of interest, enhanced production of Smad 7, an inhibitor of TGF-β, has been identified in tissue obtained from patients with IBD (J Clin Invest 2001; 108:601–9). Therefore, up-regulation of T-bet may be a critical step regulating the balance of pro- and antiinflammatory cytokines in intestinal inflammation. Several questions remain regarding the role of T-bet in Crohn disease. For example, the presence of Th1 polarization in Crohn disease has been controversial in human studies (Scand J Gastroenterol 2001(suppl); 234:29–49, Can J Gastroentol 1999; 13: 509–16, Gastroenterology 1998; 115:1595–6). In addition, the mechanisms responsible for T-bet up-regulation in Crohn disease are not known. Possibilities include an antigen-dependent pathway, through an increase in IL-12/STAT4 signaling, and an antigen-independent pathway, through autoactivation (Science 2001; 292:1907–10). Several lines of evidence support the former pathway. First, the lamina propria of patients with Crohn disease contains an increased number of activated macrophages available to upregulate T-bet in an antigen-dependent manner (Gut 1994; 35:669–674, Clin Exp Immunol 1995; 100:291–297, Am J Pathol 2001; 158:110–1109). Second, there is an increase in both IL-12 (Gut 1998; 43:735–6, Gastroenterology 1997; 112:1169–78, Am J Pathol 1998; 152:667–72) and its receptor IL-12Rβ2 in CD4+ lamina propria lymphocytes obtained from patients with Crohn disease (J Immunol 2000; 165:7234–39). However, the antigen responsible for T-bet upregulation is not known. Microbes have been implicated in the pathogenesis of both Crohn disease and ulcerative colitis, and may be involved in antigen-dependent activation of T-bet. The direct modulation of T-bet by microorganisms has not been investigated. However, modulation of the Th2 transcription factor GATA-3 by human papilloma virus has recently been identified (Am J Pathol 2002; 160:1945–51). In conclusion, the article by Neurath and colleagues is an elegant study providing support for a role of Th1 lymphocytes in Crohn disease through alteration in T-bet, a transcription factor involved in the commitment of CD4+ lymphocytes to the Th1 phenotype. Therefore, modulation of T-bet signaling may prove to be a useful therapeutic modality in the treatment of patients with chronic inflammatory bowel disease. Further studies are now required to determine what mediates the increased expression of T-bet in Crohn disease. Sylvie Lebel Nicola L. Jones Division of GI/Nutrition Hospital for Sick Children Departments of Pediatrics and Physiology University of Toronto Toronto, Ontario

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