CD8+ T cell-mediated delayed rejection of orthotopic guinea pig cornea grafts in mice deficient in CD4+ T cells.

PURPOSE To determine the immunopathogenesis of delayed orthotopic corneal xenograft rejection in mice deficient in the xenoreactive CD4+ T cells that mediate acute rejection. METHODS CB.17 SCID and BALB/c mice were used as recipients of orthotopic cornea grafts obtained from strain 13 guinea pigs. Before transplantation, SCID recipients, which do not normally reject guinea pig cornea grafts, were reconstituted with spleen cells (whole, CD4-depleted, CD4/CD8-depleted) or purified CD8+ T cells from normal BALB/c donors. Graft survival was assessed by clinical examination, and median survival times (MST) were calculated. Lymphocytes from mice that rejected guinea pig cornea grafts were analyzed in vitro for their capacity to respond to guinea pig xenoantigens and to lyse guinea pig target cells. RESULTS SCID mice reconstituted with whole spleen cells from BALB/c donors rejected guinea pig corneas with a vigor identical with that of normal BALB/c mice (MST = 15 and 14 days, respectively), whereas SCID mice reconstituted with CD4-depleted BALB/c spleen cells rejected guinea pig corneas in a delayed fashion (MST = 27 days), as did SCID mice reconstituted with purified CD8+ T cells from BALB/c donors. Although CD8+ T cells from rejector mice failed to lyse guinea pig target cells in vitro, the T cells proliferated and secreted IFN-gamma in response to in vitro stimulation with guinea pig xenoantigens. CONCLUSIONS Guinea pig cornea xenografts that avoid acute rejection in CD4+ T cell-depleted mice are vulnerable to rejection by CD8+ T cells. Effector CD8+ T cells destroy corneal xenografts through release of proinflammatory mediators (IFN-gamma) rather than by cytotoxicity.