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 that dendritic cells are 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 resulting in small intestinal inflammation, and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

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Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$757,624
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Department
Type
DUNS #
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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
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, Francoise; Davidson, Todd S; Kahle, Erin et al. (2008) The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29:79-89