IL-10 IMPACTS AUTOIMMUNE DIABETES VIA A CD8(-CELL PATHWAY CIRCUMVENTING THE REQUIREMENT FOR CD4(+) T-LYMPHOCYTES AND B-LYMPHOCYTES() T)

IL-10 is essential for are early phase of diabetes in nonobese diabeti c (NOD) mice, but later becomes protective against ifs development. Th e mechanism by which IL-10 mediates the pathway to diabetes in these m ice is unknown, Herein, we dissected the cellular and costimulation re quirements for diabetes in transgenic (tg) NOD mice that expressed IL- 10 in their pancreatic islets (IL-10-NOD mice), We found that IL-10 al one did not cause diabetes because the offspring (IL-10-NOD-scid mice) from backcrosses of IL-10-NOD mice with NOD-scid mice had no diabetes . Moreover, these IL-10-NOD-scid mice were free of lymphocytic infiltr ation. Treatment of IL-10-NOD mice with depleting anti-CD4 mAb or cont rol mAb had no effect are diabetes. Surprisingly, depletion of CD8(+) T cells by treatment with the corresponding mAb inhibited diabetes wit hout attenuating insulitis, demonstrating a critical role for CD8(+) T cells in the disease process. interestingly, B cell-deficient IL-10-N OD mice readily developed diabetes with kinetics and incidence similar to those observed in wild-type mice, demonstrating that B lymphocytes as APCs were not required in the disease process. Administration of a nti-CD40 ligand (CD40L) mAb did not prevent disease, indicating that C D40/CD40L costimulation is not required for diabetes in IL-10-NOD mice , immunization of IL-10-NOD mice with CFA or heat-shock protein 65, kn own to block diabetes in NOD mice, had no effect on their diabetes. We demonstrate that IL-10 contributes early to the pathology of diabetes via a CD8(+) T cell pathway, eliminating the requirement for B lympho cytes and CD40-CD40L costimulation, Our findings provide a mechanism f ar the participation of IL-10 in the early development of diabetes.