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

Authors

  • Françoise Meylan,

    1. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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  • Arianne C. Richard,

    1. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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  • Richard M. Siegel

    1. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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Richard M. Siegel
Immunoregulation Section, Autoimmunity Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
Building: 10, Room: 13C103A
Bethesda, MD 20892, USA
Tel.: +1 301 496 3761
Fax: +1 301 451 5394
e-mail: rsiegel@nih.gov

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.

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