TL1A signaling enhances the differentiation of TH9 cells and TH9-driven pathologies via STAT6 signaling pathways

The TNF family member TL1A plays an important role in the development of inflammatory bowel diseases (IBD), experimental autoimmune encephalomyelitis, and allergic lung inflammation by modulating T_H1, T_H17, and T_H2 responses. TL1A polymorphisms have been identified through genome-wide association studies to confer susceptibility to IBD and have been associated with disease severity. IBD patients with TL1A risk haplotypes have elevated expression of TL1A in peripheral blood monocytes and transgenic mice overexpressing TL1A develop spontaneous small intestinal inflammation. However, the effects of TL1A on other T_H subsets remain unknown. Recently, T_H9 cells have been identified as an independent T_H cell subset and have been implicated in allergic lung inflammation, and IBD. In this study, we identified TL1A as a strong inducer of T_H9 cell differentiation in vitro. Mechanistically, TL1A enhanced STAT6 activation via NF-kB signaling pathway that lead to enhanced binding of the transcription factor IRF4 to the Il9 promoter. Utilizing an adoptive T cell transfer model of colitis we demonstrated that T_H9 cells differentiated ex vivo in the presence of TL1A are highly pro-inflammatory in vivo and lead to more severe intestinal and lung inflammation compared to T_H9 cells as characterized by increased histoscores, cell numbers in mesenteric lymph nodes and spleens, enhanced proliferation of transferred cells, and increased IL-9, IL-13, and IL-17 production. Using blocking anti-IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Our results demonstrate that TL1A promotes T_H9 cell differentiation and function and define a role for IL-9 in TL1A-induced mucosal inflammation and potential therapeutic target in inflammatory diseases.