Glucocorticoid-Induces TNFR-Related Protein Lowers the Threshold of CD28 Costimulation in CD8+ T cells

CD28 is well characterized as a costimulatory molecule in T cell activation. Recent evidences indicate that TNFR superfamily members, including glucocorticoid-induced TNFR-related protein (GITR), act as costimulatory molecules. In this study, the relationship between GITR and CD28 has been investigated in murine CD8 T cells. When suboptimal doses of anti-CD3 Ab were used, the absence of GITR lowered CD28-induced activation in these cells whereas the lack of CD28 did not affect the response of CD8 T cells to GITR costimulus. In fact, costimulation of CD28 in anti-CD3-activated GITR/ CD8 T cells resulted in an impaired increase of proliferation, impaired protection from apoptosis, and an impaired rise of activation molecules such as IL-2R, IL-2, and IFN-. Most notably, CD28-costimulated GITR/ CD8 T cells revealed lower NF-B activation. As a consequence, up-regulation of Bcl-xL, one of the major target proteins of CD28-dependent NF-B activation, was defective in costimulated GITR/ CD8 T cells. What contributed to the response to CD28 ligation in CD8 T cells was the early up-regulation of GITR ligand on the same cells, the effect of which was blocked by the addition of a recombinant GITR-Fc protein. Our results indicate that GITR influences CD8 T cell response to CD28 costimulation, lowering the threshold of CD8 T cell activation