CD28 regulates glucocorticoid-induced TNF receptor family-related gene expression on CD4⁺ T cells via IL-2-dependent mechanisms

The glucocorticoid-induced TNF-related gene receptor (GITR) is the newest member of the costimulatory molecule family and is expressed on both resting CD4⁺CD25⁺ regulatory T (T_R) cells and activated CD4⁺ T cells. We investigated the endogenous mechanisms that regulate GITR expression on both T_R and CD4⁺ T cells, as well as the functional interaction between GITR and other costimulatory molecules. CD28 stimulation increased GITR expression on both T_R and CD4⁺ T cells via IL-2-dependent mechanisms. In addition, ligation of GITR and/or CD28 increased the level of CD4⁺ T cell proliferation and effector function under both APC-dependent and -independent conditions, suggesting that these costimulatory molecules cooperate to regulate CD4 ⁺ T cell activation and function by directly signaling to the CD4⁺ T cell. Thus, GITR may serve opposing functional roles on CD4⁺ T_R and effector cells and alterations in GITR expression and/or function may tip the balance between immune tolerance and effector function.