GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily

Abstract

Glucocorticoid‐induced TNFR‐related gene (GITR; TNFRSF18), a receptor belonging to the TNFR superfamily (TNFRSF), is activated by GITRL. GITR is expressed at low levels on resting responder T lymphocytes and is up‐regulated in T regulatory cells (Treg cells) and in activated T cells. GITRL is expressed in endothelial and antigen‐presenting cells. The cytoplasmic region of GITR has a striking homology with other TNFRSF members (4‐1BB, CD27, OX40) and binds TRAF molecules and Siva. Over recent years, the role of GITR in the development and in the pathophysiology of the immune system has been actively explored by several groups. GITR triggering induces both pro‐ and anti‐apoptotic effects, abrogates the suppressive activity of Treg cells and co‐stimulates responder T cells, with the latter activities over‐stimulating the immune system. In vivo, GITR activation causes development of autoimmune diseases and restores immune responses in a persistent retroviral infection model and in a tumor model. Intriguingly, GITR knockout mice demonstrate lower mortality in an ischemia model. The GITR‐GITRL system appears crucial in regulating immunity and warrants further study.