title: 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: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Arianne C
authors: AC
authors: Richard
authors: Experimental Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Cuiyan
authors: C
authors: Tan
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Eric T
authors: ET
authors: Hawley
authors: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Julio
authors: J
authors: Gomez-Rodriguez
authors: Department of Pediatrics and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors: Ritobrata
authors: R
authors: Goswami
authors: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Xiang-Ping
authors: XP
authors: Yang
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Anthony C
authors: AC
authors: Cruz
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Pallavi
authors: P
authors: Penumetcha
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Erika T
authors: ET
authors: Hayes
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Martin
authors: M
authors: Pelletier
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Odile
authors: O
authors: Gabay
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102;
authors: Matthew
authors: M
authors: Walsh
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; and.
authors: John R
authors: JR
authors: Ferdinand
authors: Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Fort Detrick, MD 21702.
authors: Andrea
authors: A
authors: Keane-Myers
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102;
authors: Yongwon
authors: Y
authors: Choi
authors: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: John J
authors: JJ
authors: O'Shea
authors: Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; and.
authors: Aymen
authors: A
authors: Al-Shamkhani
authors: Department of Pediatrics and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors: Mark H
authors: http://orcid.org/0000-0002-2923-8245
authors: MH
authors: Kaplan
authors: Experimental Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Igal
authors: I
authors: Gery
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; rsiegel@nih.gov.
authors: Richard M
authors: RM
authors: Siegel
authors: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Françoise
authors: F
authors: Meylan
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D016906:Interleukin-9 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000276:immunology*
chemical_list: D018793:Interleukin-13; D016906:Interleukin-9; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D015847:Interleukin-4