Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells

Abstract

Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-β), the presence of GITR+ cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs.

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…The transcriptional landscape of CD5 hi Tregs was enriched for genes associated with Treg function. To confirm these observations at the protein level, we analyzed the expression of key markers associated with Treg lineage stability and function: Foxp3, CD25, GITR, CTLA-4, and ICOS (24,(34)(35)(36)(37)(38). Similar to the RNA sequencing (RNA-seq) analysis, the Treg population was divided equally into the top 35% (CD5 hi ) and bottom 35% (CD5 lo ) of CD5 expression ( Figure 4A).…”

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

“…GITR is expressed at high levels in activated T cells and Tregs. However, a recent review article discussing data from mouse and human studies has suggested that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs) [31]. Moreover, the authors have suggested two potential new approaches for treating autoimmune diseases consisting of the in vivo expansion of GITR + Tregs by GITR-triggering drugs and in vitro expansion of autologous or heterologous GITR + Tregs to be infused in the patients [32].…”

Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted

“…GITR signaling by Fc-GITRL dimers has been also reported to enhance CD8 + T cell-mediated antitumor responses (16), but others have found that Fc-GITRL protein preferentially induces the proliferation of Treg cells rather than effector T cells (17). Each form of GITR agonist has its own curative effects in vivo, and the modulation or elimination of Treg cells seems to be crucial for GITR-mediated antitumor responses (18,19). Consequently, the effects of GITR triggering in the absence of Fcmediated signaling need to be determined.…”