Retina-Specific T Regulatory Cells Bring About Resolution and Maintain Remission of Autoimmune Uveitis

Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein (IRBP) is a model of human autoimmune uveitis. We examined whether T regulatory cells (Tregs) found in uveitic eyes are IRBP specific, functionally suppressive, and play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3 + Treg to T effector cell (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Tregs (CD4 + Foxp3 +) and up to 60% of Teffs (CD4 + Foxp3 2) were IRBP specific, whereas in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teffs from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Tregs and Teffs. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3 + Tregs play a role in the natural resolution of uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye. N atural T regulatory cells (Tregs) that are released from the thymus of normal animals soon after birth are essential for maintenance of tissue homeostasis (1, 2). Treg depletion in adulthood precipitates multiorgan autoimmune disease and death (3). Induced Tregs arise as a result of contact with Ag during adult life, but their ability to control active autoimmunity has been debated. Although Tregs were shown to be present in the target organ affected by inflammation, isolated Tregs from in-flammatory sites may be deficient functionally. Inflammatory cytokines have been implicated in this impairment of Treg function , possibly permitting ongoing and chronic inflammation in the target organ (4, 5). In the case of the eye, the situation is colored by the unique needs and properties of the ocular tissues. Due to the necessity to preserve vision that might sustain collateral damage as a result of inflammation , the healthy eye is an immunoregulatory environment that resists inflammatory processes (6). By using T cells expressing a …