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IL-22 has opposing effects in different tissues, from pro-inflammatory (skin, joints) to protective (liver, intestine) but little is known about its effects on neuronal tissue. We examined this using the induced models of experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE). During EAU, IL-22 was produced by CD4+ eye-infiltrating cells, most of which co-produced IL-17. IL-22-/- mice immunized for EAU or for EAE had exacerbated disease, as did wild type mice treated with anti-IL-22 systemically or intraocularly during the expression phase of EAU. Retinal glial Müller cells in uveitic eyes had upregulated IL-22rα1 expression. Furthermore, IL-22 upregulated IL-22rα1 on Müller cells in culture and enhanced their ability to suppress effector T cells. Finally, IL-22 injected concurrently with IL-1β into the eye inhibited IL-1-induced expression of multiple proinflammatory and proapoptotic genes in retinal tissue. Our results suggest that IL-22 can function locally within the CNS to ameliorate inflammatory damage and provide neuroprotection by affecting multiple molecular and cellular pathways.

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