Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site

• T cell activation in the gut correlates with spontaneous uveitis in R161H mice
• Elimination of gut microbiota attenuates disease and reduces T cell activation in the gut
• Presence of endogenous antigen is not required for intestinal T cell activation
• Extracts of intestinal contents signal via retina-specific TCR and trigger uveitis

SummaryActivated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated.

Graphical AbstractFigure optionsDownload high-quality image (141 K)Download as PowerPoint slide