Local “On-Demand” Generation and Function of Antigen-Specific Foxp3+ Regulatory T Cells

Abstract

Extrathymically derived regulatory T cells (iTregs) protect against autoimmunity to tissue-specific antigens (Ag). However, whether Ag-specific iTreg generation and function is limited to secondary lymphoid tissue or whether it can occur within the tissue-specific, local environment of the cognate Ag remains unresolved. Mice expressing beta-galactosidase (βgal) on a retina specific promoter (βgal mice) in conjunction with mice expressing green fluorescent protein (GFP) and diphtheria toxin (DTx) receptor (DTR) under control of the FoxP3 promoter, and βgal-specific T cell receptor transgenic (BG2) mice were used to examine this question. Local depletion (ocular DTx), but not systemic depletion (intra-peritoneal DTx), of βgal-specific iTregs enhanced experimental autoimmune uveoretinitis induced by activated βgal-specific effector T cells. Injections of small amounts of βgal into the anterior chamber of the eye produced similar numbers of βgal-specific iTregs in the retina whether or not the mouse was depleted of pre-existing, circulating Tregs. Together these results suggest that protection from tissue-specific autoimmunity depends on the function of local Ag-specific iTregs, and that the retina is capable of local, “on-demand” iTreg generation that is independent of circulating Tregs.

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

“…DT was injected into one eye and PBS was injected into the contralateral eye to control for the nonspecific proinflammatory effects of the anterior chamber injection. The functional efficacy of such AC injection has been reported (8). Each mouse received 3 DT injections during a one-week period.…”

“…This property has been postulated for a long time based on the ability of ocular fluids to induce Treg function in conventional T cells (6), and has recently been demonstrated directly to be an inherent property of the living eye by using mice that express a TCR recognizing an antigen present within the retina (7, 8). The question then arises, how can uveitis occur if the eye can convert conventional T cells to Tregs?…”

“…Such T cells, which have been primed in the periphery and have acquired the ability to actively break down the blood-retinal barrier, cannot be converted to Tregs within the eye. Although recently evidence has been presented in favor of a tiny eye-resident population of Tregs that raise the threshold of susceptibility to uveitis (8), the activated effector T cells can clearly overcome local inhibitory mechanisms and induce disease. Furthermore, the inflamed eye is less efficient in converting even naïve T cells to Tregs (7).…”

“…This process, which is part of the phenomenon known as ocular immune privilege, is promoted by high concentrations of TGF-β and retinoic acid that are constitutively present in the eye. Other studies indicated that a tiny population of resident Tregs is present in the healthy eye and may constitute part of ocular immune privilege (8). Nevertheless, the eye is subject to destructive inflammation precipitated by uveitogenic T cells activated outside the eye, which have acquired the ability to actively cross the blood-retinal barrier.…”

“…Though the small population of Tregs within the healthy eye raises the threshold of development of retinal autoimmunity (8), their presence does not clarify the role of Tregs after this threshold has already been broken and autoimmunity has begun. The present study deals with this question.…”