DR3, also known as TRAMP, LARD, WSL-1, or TNFRSF25, is a death-domain containing tumor necrosis receptor that is the closest homolog to TNF-receptor 1, which is a key transducer of inflammatory responses in the innate immune system. DR3 however, is primarily expressed in T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. In studies published this year, we have shown that DR3 is the critical receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell priming. Despite its role in costimulation, DR3 is not required for T cell polarization into Th1, Th2 or Th17 effector subtypes or after priming with model antigens or Toxoplasma gondii. However, DR3 is required on T cells for immunopathology, local T cell accumulation and cytokine production in autoimmune and allergic disease models that depend on diverse effector T cell subsets. DR3 is required for efficient T-cell infiltration and immunopathology in inflamed tissues and may be a promising therapeutic target for autoimmune diseases in which T-cells play a pathogenic role such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Type-1 diabetes, autoimmune thyroid disease, and others. To better study the type of immune responses stimulated by TL1A, we generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13 dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal TCR repertoire, suggesting that they are driven by components in the intestinal flora. FoxP3+ Treg were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Treg. Finally, blocking TL1A-DR3 interactions abrogates TNBS-colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and IL-13 responses that results in small intestinal inflammation and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$1,110,500
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
City
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Country
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Richard, Arianne C; Peters, James E; Lee, James C et al. (2016) Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Med 8:76
Gomez-Rodriguez, Julio; Meylan, Françoise; Handon, Robin et al. (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857
Wilhelm, Christoph; Harrison, Oliver J; Schmitt, Vanessa et al. (2016) Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection. J Exp Med 213:1409-18
Richard, Arianne C; Ferdinand, John R; Meylan, Françoise et al. (2015) The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. J Leukoc Biol 98:333-45
Richard, Arianne C; Tan, Cuiyan; Hawley, Eric T et al. (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. J Immunol 194:3567-82
Richard, Arianne C; Lyons, Paul A; Peters, James E et al. (2014) Comparison of gene expression microarray data with count-based RNA measurements informs microarray interpretation. BMC Genomics 15:649
Pereira-Manfro, Wania F; Ribeiro-Gomes, Flavia L; Filardy, Alessandra Almeida et al. (2014) Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection. J Leukoc Biol 95:347-55
Meylan, F; Hawley, E T; Barron, L et al. (2014) The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal Immunol 7:958-68
Meylan, Françoise; Richard, Arianne C; Siegel, Richard M (2011) TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunol Rev 244:188-96
Meylan, F; Song, Y-J; Fuss, I et al. (2011) The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol 4:172-85

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