Melanocortin 5 receptor expressed by APC mediates activation of Treg cells during experimental autoimmune uveoretinitis (166.21)

Abstract

Abstract We previously showed that IRBP-specific memory Treg cells (Tregs) emerge in the spleen of experimental autoimmune uveoretinitis (EAU) recovered mice and are necessary to protect from a memory immune response to IRBP. Induction of these memory Tregs require melanocortin 5 receptor (MC5r), and APC also from EAU recovered mice. We investigated if the T cell or the APC requires MC5r in the induction of memory Tregs that emerge during EAU resolution. EAU was induced in C57BL/6 wild type and MC5r(-/-) mice with IRBP, the spleen cells were collected througout EAU to assay for IRBP stimulated T cell cytokine production of IFN-γ, IL-17, and TGF-β. We observed a MC5r dependent shift in the cytokine profile from effector cytokines, Th1 and Th17, in the beginning of EAU to regulatory. MC5r was required for a consistent increase in TGF-β production through the course of EAU, continuing through resolution. Isolated APC from the spleens of EAU-recovering mice were able to convert IRBP-specific MC5r(-/-) Th1 cells into Tregs, that are capable of suppressing EAU when adoptively transferred into mice with EAU. We have found that during the course of EAU a nonconventional APC emerges in the spleen. This APC requires expression of MC5r to promote induction of memory Tregs. Therefore, stimulation of the melanocortin pathway during EAU is required for the reestablishment of immune tolerance to ocular autoantigens.