• Arianne C Richard, Cuiyan Tan, Eric T Hawley, Julio Gomez-Rodriguez, Ritobrata Goswami, Xiang-Ping Yang, Anthony C Cruz, Pallavi Penumetcha, Erika T Hayes, Martin Pelletier, Odile Gabay, Matthew Walsh, John R Ferdinand, Andrea Keane-Myers, Yongwon Choi, John J O'Shea, Aymen Al-Shamkhani, Mark H Kaplan, Igal Gery, Richard M Siegel, and Françoise Meylan.
• Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
• J. Immunol. 2015 Apr 15; 194 (8): 3567-82.

AbstractThe 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. Copyright © 2015 by The American Association of Immunologists, Inc.

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