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.

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.

• Authors: 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, Françoise Meylan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 8 Pg. 3567-82 (Apr 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25786692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Interleukin-13
• Interleukin-9
• Receptors, Tumor Necrosis Factor, Member 25
• Tnfrsf25 protein, mouse
• Tnfsf15 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 15
• Interleukin-4

Topics

• Animals
• Asthma (genetics, immunology, pathology)
• Cell Differentiation (genetics, immunology)
• Inflammation (genetics, immunology, pathology)
• Interleukin-13 (genetics, immunology)
• Interleukin-4 (genetics, immunology)
• Interleukin-9 (genetics, immunology)
• Mice
• Mice, Knockout
• Receptors, Tumor Necrosis Factor, Member 25 (genetics, immunology)
• Signal Transduction (genetics, immunology)
• T-Lymphocytes, Helper-Inducer (immunology, pathology)
• Tumor Necrosis Factor Ligand Superfamily Member 15 (genetics, immunology)