Conversion of Alloantigen-Specific CD8⁺ T-Cell Anergy to T-Cell Priming through In Vivo Ligation of Glucocorticoid-Induced Tumor Necrosis Factor Receptor.

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced tumor necrosis factor receptor (GITR) in a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-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 towards aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8⁺ T cells from being anergic. Functionally active donor CD8⁺ T cells produced high levels of IFN-γ and had an elevated CTL activity against host antigens. In in vitro MLR, anergic responder CD8⁺ T cells were generated and DTA-1 stimulated the activation of responder CD8⁺ T cells that were fated to be anergic. We further confirmed in vivo that donor CD8⁺ T cells, but not donor CD4⁺ T cells, are responsible for the DTA-1-mediated conversion of cGVHD to aGVHD in a CD4⁺CD25⁺ regulatory T cell-independent manner. These results indicate that donor CD8⁺ T-cell anergy is a restriction factor in the development of aGVHD and that GITR stimulation prevent CD8⁺ T-cell anergy by activating CD8⁺ T cells prone to anergy. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD versus aGVHD and as a target for therapeutic intervention in a variety of related diseases.