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.

Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

“…However, cross-linking of GITR was later shown to co-stimulate both Treg and Teff [50][51][52]. Therefore, the precise mechanistic involvement of GITR in Treg-mediated suppression remains under scrutiny [49]. Future lines of research should address Treg suppression of gd-T-cell functions in animal models of tumor rejection, where the potential of GITR modulation should also be assessed and the dynamics of these two lymphocyte populations in human pathology examined, particularly as circulating human Treg frequencies and gd-T-cell numbers have been inversely correlated in cancer patients [24].…”

“…However, cross-linking of GITR was later shown to co-stimulate both Treg and Teff [50][51][52]. Therefore, the precise mechanistic involvement of GITR in Treg-mediated suppression remains under scrutiny [49].…”

“…Importantly, our results demonstrate that the modulation of GITR signals can partially reverse the suppressive effect of Treg on gd-T-cell proliferation and cytokine production. GITR is a Treg-biased gene product [47,48] that binds a ligand (GITR-L) expressed on endothelial and APC [49]. The administration of a-GITR mAb was previously shown to induce autoimmune manifestations in mice [48], and to abrogate Treg-mediated suppression of Teff activity in vitro [47,48].…”

Intracellular Signals of T Cell Costimulation

“…TRAFs were initially discovered through their ability to bind to the p75 TNFR and were classified as a gene family based on a conserved domain on the C terminus, i.e., the TRAF domain and they had been characterized as TRAFs 1 to 6 (25). The TRAF domain enables TRAFs to interact with various receptors, including members of TNFRSF and multiple intracellular signaling molecules (27). OX40 can function with TRAF2 and mediated downstream signaling pathways (28), whereas TRAF1 acts as a modulator of TRAF2 signaling, TRAF3 serves as an inhibitor of TRAF2/5-mediated NF-κB activation (29,30).…”

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

“…[22][23][24][25][26][27][28] GITR, a member of the tumor necrosis factor receptor superfamily, is constitutively expressed on Tregs but it is also expressed at low levels on multiple immune cells, including T cells, natural killer cells and B cells in which it is upregulated on activation. 7,23,[29][30][31] Treatment of mice with an agonistic anti-GITR mAb (anti-GITR), clone DTA-1, alone has been shown to cause exacerbated autoimmune disease in susceptible mice and enhanced anti-viral and anti-tumor immune responses in disease-bearing animals. 22,[24][25][26][27][28] When combined with DNA immunization against xenogeneic melanoma-related antigens, DTA-1-treated mice showed increased T-cell responses and protection from tumor challenge.…”