Breaking of CD8/sup +/ T-cell anergy through in vivo ligation of GITR

Peripheral T-cell anergy is an important tolerance mechanism. Using a murine model of chronic systemic lupus erythematosus (SLE)-like graft-versus-host disease (cGVHD), we demonstrate that donor CD8/sup +/ T cells rapidly become hyporesponsive in the recipient mouse. Further we find that a single dose of an agonistic antibody against GITR, a member of the TNF receptor superfamily, prevents donor CD8/sup +/ T-cell anergy. The subsequent functional recovery of donor CD8/sup +/ T cells results in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8/sup +/ T-cell anergy is a restriction factor in the development of aGVHD. In addition, ligation of GITR restores the cytotoxic function of anergic donor CD8/sup +/ T cells in established cGVHD. These data suggest GITR as an important costimulatory elated diseases.