Richard, Arianne C.Tan, CuiyanHawley, Eric T.Gomez-Rodriguez, JulioGoswami, RitobrataYang, Xiang-pingCruz, Anthony C.Penumetcha, PallaviHayes, Erika T.Pelletier, MartinGabay, OdileWalsh, MatthewFerdinand, John R.Keane-Myers, AndreaChoi, YongwonO'Shea, John J.Al-Shamkhani, AymenKaplan, Mark H.Gery, IgalSiegel, Richard M.Meylan, Françoise2017-09-222017-09-222015-04-15Richard, A. C., Tan, C., Hawley, E. T., Gomez-Rodriguez, J., Goswami, R., Yang, X., … Meylan, F. (2015). The TNF-family ligand TL1A and its receptor DR3 promote T-cell mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9 producing T cells. Journal of Immunology (Baltimore, Md. : 1950), 194(8), 3567–3582. http://doi.org/10.4049/jimmunol.14012201550-6606https://hdl.handle.net/1805/14169The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.en-USPublisher PolicyAsthmaimmunologyCell DifferentiationInterleukin-9Receptors, Tumor Necrosis Factor, Member 25T-Lymphocytes, Helper-InducerTumor Necrosis Factor Ligand Superfamily Member 15Article