Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8(+) T-cell clones in vivo

NOD mouse-derived beta-cell-specific cytotoxic T-cell (beta-CTL) clones are diabetogenic in adult NOD mice, but only if co-injected with splenic CD4(+) T-cells from diabetic animals, This investigation was initiated to determine whether infiltration of pancreatic islets by beta-CTL is a major histocompatibility complex (MHC) class I-restricted response, and whether beta-CTL has a direct cytopathic effect on beta-cells in vivo. Pancreatic islets from BALB/c (H-2(d)) or B6 (H-2(b)) mice were transplanted under the renal capsule of streptozotocin (STZ)-induced diabetic (NOD x BALB/c) F1 (H-2K(d), H-2D(d,b)) or (NOD x B6) F1 (H-2K(d,b), H-2D(b)) mice, respectively, H-2K(d)-restricted beta-CTL clones from NOD mice were transfused into euglycemic mice within 3 days after transplantation. In all of the H-2(d) islet-grafted (NOD x BALB/c) F1 mice that received the beta-CTL clones, the beta-CTLs homed into the grafts, recruited host Mac-1(+) cells and CD4(+) and CD8(+) T-cells, and caused diabetes within 7 days, In contrast, none of the H-2(b) islet-grafted (NOD x B6) F1 mice who received the beta-CTL clones and none of the H-2(d) islet-grafted (NOD x BALB/c) F1 mice who received a non-beta-cell cytotoxic CTL clone (N beta-CTL) developed graft. inflammation or diabetes, Depletion of CD4(+) T-cells in H-2(d) islet-grafted (NOD x BALB/c) F1 mice did not prevent beta-CTL clone-induced diabetes but reduced its severity. In contrast, when the beta-CTL clones were injected >8 days after transplantation, none of the H-2(d) islet-grafted (NOD x BALB/c) F1 mice became diabetic or developed graft inflammation, We conclude that (1) islet-derived beta-CTLs can destroy beta-cells in vivo; (2) infiltration of grafted islets by beta-CTLs is an MHC class I-restricted response; (3) beta-CTLs can recruit naive CD4(+) T-cells to the site, leading to further beta-cell damage; and (4) revascularized islet grafts are, Like pancreatic islets of irradiated adult NOD mice, ''sequestered'' from circulating beta-CTLs.