The TNF family member TL1A promotes Th9 differentiation and Th9-mediated immunopathology (LYM3P.733)

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells through its receptor DR3 (Tnfrsf25). Currently known effects of TL1A on T cell differentiation or systemic immune responses cannot account for the resistance of Tnfrsf25-/- mice to diverse animal models of autoimmune and allergic inflammation. IL-9 is a cytokine that promotes inflammatory and allergic immune responses and is expressed by a distinct subset of T cells early after T cell activation or restimulation. We have found that TL1A potently promotes generation of T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. Unlike the TNF family member OX40 ligand, TL1A increases Th9 differentiation independently of STAT6 and the TNF-signaling adaptor TRAF6. Instead, TL1A affects Th9 differentiation through enhancing IL-2-dependent STAT5 activation and allowing increased binding to the IL-9 promoter. In two models of allergic asthma, we demonstrate that Tnfrsf25-/- mice have reduced disease severity accompanied by fewer IL-9 producing T cells in the lung. In addition to promoting Th9 differentiation, we find that TL1A enhances pathogenicity in Th9 transfer models of both uveitis and allergic asthma, where endogenous TL1A signaling is required for maximal pathology and IL-9 production at the site of inflammation. Taken together, these data identify TL1A as a novel cytokine that promotes Th9 differentiation and pathogenicity and as a possible therapeutic target in diseases dependent on IL-9.