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.