Conversion of Alloantigen-Specific CD8 super(+) T Cell Anergy to CD8 super(+) T Cell Priming through In Vivo Ligation of Glucocorticoid-Induced TNF Receptor

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8 super(+) T cell anergy. Functionally active donor CD8 super(+) T cells produced high levels of IFN- gamma and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8 super(+) T cells were generated, and DTA-1 stimulated the activation of these anergic CD8 super(+) T cells. We further confirmed in vivo that donor CD8 super(+) T cells, but not donor CD4 super(+) T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8 super(+) T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8 super(+) T cell anergy by activating donor CD8 super(+) T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.