Activation of autoreactive T cells by endogenous microflora induces spontaneous autoimmunity in the immunologically privileged retina (BA8P.130)

Abstract

Abstract Autoimmune uveitis (AU) has an incidence similar to multiple sclerosis, it develops spontaneously and is a major cause of blindness. We hypothesized that AU could be triggered by endogenous microbiota in view of anecdotal evidence linking AU to systemic infections. We tested this in R161H mice, a new model of AU developed in our lab. R161H mice express a transgenic T cell receptor (TCR) specific to retinal protein IRBP and develop spontaneous uveitis starting at 4 weeks of age. R161H mice treated with an antibiotic cocktail, or reared under germ free conditions, had a significant delay in disease onset and intensity compared to controls, as well as fewer IL-17-secreting T cells in the gut LP. Notably, conventionally housed R161H mice consistently displayed 2-5x more Th17 cells in their LP compared to WT littermates, even when crossed onto an IRBP-deficient background. Compared to polyclonal T cells, R161H TCR transgenic T cells were more readily activated by extracts of gut contents in vitro and adopted the Th17 phenotype in the gut with higher frequency in vivo. Experiments utilizing Nur77 reporter mice and pZap70, revealed clear evidence that IRBP-specific T cells receive an activation signal through their TCR in the gut. These data not only have implications for etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microflora may be a more common trigger of autoimmune diseases than is currently appreciated