Immune responses to retinal self-antigens in CD25(+)CD4(+) regulatory T-cell-depleted mice

PURPOSE: Prior work has shown that autoimmune uveoretinitis develops spontaneously in CD25(+)CD4(+) regulatory T-cell-depleted mice (Tr-depleted mice). In this study, the generation of autoantibodies and autoreactive T-cells specific to retinal antigens was examined in Tr-depleted mice with uveoretinitis, and the pathogenic and immunogenic abilities of the autoreactive T cells were evaluated. METHODS: Tr-depletion was achieved in (C57BL/6 x A/J) F1 (B6A) mice by thymectomy on day 3 of life followed by intraperitoneal injection of an anti-CD25 mAb. At 6 months of age, autoantibodies to the retina were evaluated by indirect immunofluorescence, and total IgG2a levels in sera were assessed by ELISA. The pathogenic abilities of the splenic T cells were examined by adoptive transfer to syngeneic nu/nu mice, and the proliferation responses and the secretion of granulocyte-macrophage-colony-stimulating factor (GM-CSF), IFN-gamma, and IL-10 on stimulation by retinal self-antigens was also evaluated. RESULTS: Autoantibodies to the retinal photoreceptor cell layer were detected in Tr-depleted mice, and the titers correlated well with the grades of inflammatory lesions. The splenic CD4(+) T cells of Tr-depleted mice induced uveoretinitis in the recipients by adoptive transfer and exhibited proliferative responses and secretion of IFN-gamma, but not of IL-10, by in vitro stimulation with S-Ag and interphotoreceptor retinoid-binding protein (IRBP). Moreover, the total IgG2a level in serum was markedly and significantly augmented in Tr-depleted mice. CONCLUSIONS: The results suggest that in Tr-depleted mice in which uveoretinitis develops, S-Ag and IRBP-specific T cells are spontaneously sensitized and shifted to a Th1-phenotype. These sensitized T cells may account for the development of autoimmune uveoretinitis in Tr-depleted mice.