TL1A and its receptor DR3 in normal and autoimmune T cell responses

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

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 inflammatory bowel disease. All TNF-family cytokines are synthesized as type II transmembrane proteins, and most are cleaved by metalloproteinases, releasing soluble cytokine trimers into the extracellular space. We generated TL1A transgenic mice expressing an uncleavable form of TL1A lacking the metalloproteinase cleavage site in T cells (mTL1A transgenic mice). We found that both membrane restricted and soluble TL1A promoted ILC2-mediated allergic intestinal inflammation TL1A. We identified the TNSF15 IBD risk locus as a cis-eQTL, controlling TL1A gene expression. Given the role of TL1A as a T cell costimulator, and the elevation of TL1A expression in IBD intestinal biopsy tissue, one might assume that the risk allele would increase TL1A expression. Surprisingly, using two independent genotyped cohorts of individuals with andwithout IBD, we found that the TNFSF15 risk haplotype decreased, rather than increased, TL1A expression at the RNA level. We have also generated DR3 knockout mice and studies are underway to define the role DR3 in models of arthritis. In related collaborative work, we also investigated a bone disease, melorheostosis and identified mutations MAPK2K1.