Glucocorticoid-Induced TNF Receptor Functions as a Costimulatory Receptor That Promotes Survival in Early

Glucocorticoid-induced TNFR (GITR) is a member of the TNFR family that can inhibit the suppressive function of regulatory T cells and promote the survival and activation of T cells. However, little is known about the molecular mechanisms regulating T cell survival and activation downstream of GITR. To gain further insight into the cellular events and signaling pathways triggered by GITR, survival, proliferation, and cytokine production as well as activation of MAPKs and NF-B were monitored after cross-linking of the receptor on naive and activated T cells. GITR cross-linking provided costimulation of naive and activated T cells and resulted in activation of MAPKs and NF-B. Although GITR-induced signaling pathways augmented the survival of naive T cells, they were not sufficient to inhibit activation-induced cell death triggered by CD3 cross-linking of activated T cells. Differences in the contributions of GITR to cell survival between naive and activated T cells suggest that the receptor triggers specific pathways depending on the activation state of the T cell. The Journal of Immunology, 2005, 174: 7869–7874. T he TNFR-related protein glucocorticoid-induced TNFR(GITR)3 is highly expressed on regulatory T (Treg) cellsand has been suggested to be a marker for these lympho-cytes (1). In addition, GITR is expressed at low levels on naive T cells, and GITR expression is up-regulated upon activation (2). GITR has been suggested to regulate survival, proliferation, and effector function(s) of T cell subsets (1–6). In particular, GITR has been implicated in inhibiting the function of CD4/CD25 Tre