4-lBB-mediated amelioration of experimental autoimmuneuveoretinitis is caused by indoleamine2,3-dioxygenase-dependent mechanisms

摘要

Interphotoreceptor retinoid binding protein (IRBP)-induced experimental autoimmune uveoretinitis (EAU) is a CD4+ T cell-mediated autoimmune disease. Development of EAU is inhibited by treatment with an agonistic anti-4-lBB mAb. Even established EAU was alleviated by anti-4-lBB mAb. However, inhibition of 4-1BB/4-1BB ligand (4-1BBL) interaction does not suppress the development of EAU. It appears that cross-linking of 4-IBB evokes an active antigen-specific suppression mechanism rather than merely blocking 4-1BB/4-1BBL interaction. We found that administration of anti-4-lBB mAb induced massive clonal expansion of CDllc+CD8+ T cells that produced IFN-y, resulting in accumulation of a high level of indoleamine 2,3-dioxygenase (IDO) in CD1 lc+ dendritic cells. 4-1BB-mediated suppression of EAU was reversed by the pharmacological IDO inhibitor, 1-methyl-tryptophan (1-MT). These studies demonstrate that suppression of EAU results from antigen-driven, 4-lBB-mediated expansion of novel CDllc+CD8+ T cells that suppress antigen-specific CD4+ T cells via an IDO-dependent mechanism