Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn’s disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag−/− , Rag−/− mice lacking DR3 in all cell types (Rag−/−Dr3−/−), or Rag−/− mice lacking DR3 only on fibroblasts (Rag−/−Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag−/− mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag−/−Dr3−/− demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag−/−, Rag−/−Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.

The protective effects of SI-IELs in DSS-induced colitis were partly accomplished by γδ T cells and could be mediated by TGF-β but were not associated with IFN-γ. Oral tolerance strengthens the suppressive effects of regulatory subsets in SI-IELs.

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Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag −/− , Rag −/− mice lacking DR3 in all cell types (Rag −/− Dr3 −/−), or Rag −/− mice lacking DR3 only on fibroblasts (Rag −/− Dr3 ∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag −/− mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag −/− Dr3 −/− demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag −/− , Rag −/− Dr3 ∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects. Death Domain Receptor 3 (DR3; TNFRSF25) is the only know receptor for TL1A (TNFSF15) 1-3. This cytokinereceptor pair controls a vast array of cellular effects, including propagation of inflammatory functions, adaptive immune cell expansion, and regulation of cell development and apoptosis: DR3 can upregulate NF-KB-dependent anti-apoptotic proteins such as c-IAP2 4. Furthermore, it can promote T cell inflammatory responses and cytokine production 5-7. In contrast, DR3's developmental and regulatory functions include induction of FADD-and caspase-8-dependent apoptosis and thymic negative selection 8,9. These diverse functions are compounded by the variety of cells that can elaborate TL1A in response to multiple stimuli: dendritic cells/macrophages responding to bacterial and immune complexes; endothelial cells induced by IL-1β and TNFα; as well as lymphoid lineage cells 10-13. Pertaining to IBD, genetic variants of TNFSF15 show elevated TL1A host expression, and are associated with a severe Crohn's Disease (CD) phenotype that features intestinal fibrostenosis and need for surgery 14-16. Consistent with human IBD, TL1A transgenic mice develop spontaneous ileitis and intestinal collagen deposition that is exaggerated under colitigenic conditions and results in severe inflammation and fibrosis 17-19. Neutralizing anti-TL1A monoclonal antibodies attenuate these effects, reducing in...