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

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. SiegelFrançoise Meylan

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)3567-3582
Number of pages16
JournalJournal of Immunology
Volume194
Issue number8
DOIs
StatePublished - Apr 15 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Richard, A. C., Tan, C., Hawley, E. T., Gomez-Rodriguez, J., Goswami, R., Yang, X. P., Cruz, A. C., Penumetcha, P., Hayes, E. T., Pelletier, M., Gabay, O., Walsh, M., Ferdinand, J. R., Keane-Myers, A., Choi, Y., O'Shea, J. J., Al-Shamkhani, A., Kaplan, M. H., Gery, I., ... 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, 194(8), 3567-3582. https://doi.org/10.4049/jimmunol.1401220