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

Abstract

Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal antigen IRBP is a model of human autoimmune uveitis. We examined whether T regulatory (Treg) cells found in uveitic eyes are (i) IRBP specific, (ii) functionally suppressive, and (iii) play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3+ Treg to T effector (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Treg (CD4+Foxp3+) and up to 60% of Teff (CD4+FoxP3−) cells were IRBP-specific, while in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teff 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 Treg and Teff cells. 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.

Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection

“…This result suggests that enhanced severity of EAU in mice with IRF8-deficient CD4 + T cells derived, in part, from the expansion of Th17 cells. Treg cells have recently been shown to bring about resolution of autoimmune uveitis (25). We therefore examined whether severe EAU in the CD4-IRF8KO mice could have resulted from perturbation of the levels of Tregs.…”

“…It is therefore noteworthy that the marked decrease of Th1 cells in CD4-IRF8KO mice with exacerbated uveitis is consistent with the notion that Th1 cells may have a protective role in uveitis (13, 39). In contrast to the pathogenic roles played by Th17 cells in human and mouse uveitis (13, 39), Treg cells are immunosuppressive and have recently been shown to be effective in ameliorating EAU (25). We show here that the enhanced EAU pathology seen in CD4-IRF8KO also correlated with a small but significant reduction in the levels of Foxp3 + Treg cells.…”

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…This may explain, in part, the disparity between these reports. CD4 + CD25 + Tregs were demonstrated to play an important role in controlling the occurrence of autoimmune diseases (55)(56)(57). Activated Tregs prevent or attenuate EAU (58)(59)(60).…”

Autoreactive T Cells in Immunopathogenesis of TB-Associated Uveitis

“…Previous studies on human uveitis have demonstrated a lowered Treg response in the peripheral circulation in active EAU as well as TBU. 16,34 The role of autoimmunity in TB pathogenesis has generated significant interest of late. 35 The paucibacillary nature of TB granulomas, presence of autoantibodies in TB patients, response to anti-TB therapy in uveitis, and inflammatory polyarthritis (Poncet's disease) even in the absence of mycobacteria, and striking histopathologic similarities between TB and sarcoidosis, are some of the arguments favoring autoimmune mechanisms in TB pathogenesis.…”