Cutting Edge: Ligation of the Glucocorticoid-Induced TNF Receptor Enhances Autoreactive CD4⁺ T Cell Activation and Experimental Autoimmune Encephalomyelitis

The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4⁺ CD25⁺ T regulatory (T_R) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139-151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of T_R cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4⁺ CD25^- T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4⁺ T cell activation, proliferation, and cytokine production in the absence of T_R cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates T_R cells and increases CD4⁺ CD25^- T cell effector function, thus enhancing T cell immunity.