TL1A and DR3, a TNF family ligand‐receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation

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Abstract
Summary: DR3 (TNFRSF25) is a member of the tumor necrosis factor receptor (TNFR) superfamily expressed primarily on lymphocytes and is a receptor for the TNF family cytokine TL1A (TNFSF15). DR3 costimulates T‐cell activation, but it is unique among these receptors in that it signals through an intracytoplasmic death domain and the adapter protein TRADD (TNFR‐associated death domain). TL1A costimulates T cells to produce a wide variety of cytokines and can promote expansion of activated and regulatory T cells in vivo. Studies in mice deficient in DR3 or TL1A or in animals treated with antibodies that block the activity of TL1A have revealed a specific role for DR3 in enhancing effector T‐cell proliferation at the site of tissue inflammation in autoimmune disease models. DR3 appears to be required in autoimmune disease models dependent on a variety of different T‐cell subsets and also invariant natural killer T (iNKT) cells. Chronic expression of TL1A induces a distinct interleukin‐13‐dependent pathology in the small intestine marked by goblet cell hyperplasia and other features associated with allergic and anti‐parasitic responses. These studies suggest that TL1A may be a viable target for therapies designed to inhibit the T‐cell‐dependent component of diverse autoimmune diseases.