TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation.
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.
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Françoise
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Meylan
Arianne C
AC
Richard
Richard M
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Siegel
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053199:TNF Receptor-Associated Death Domain Protein; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15