Abstract
BackgroundWe previously reported that the peripheral regulatory T cells (pTregs) generated ‘on-demand’ in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Here, we expanded these findings by examining whether locally generated, locally acting pTregs were protective against spontaneous autoimmunity and autoimmunity mediated by interphotoreceptor retinoid-binding protein (IRBP). We also examined the APC capacity of retinal DC in vivo.MethodsTransgenic (Tg) mice expressing diphtheria toxin receptor (DTR) and/or green fluorescent protein (GFP) under control of the endogenous FoxP3 promoter (GFP only in FG mice, GFP and DTR in FDG mice) or the CD11c promoter (GFP and DTR in CDG mice) were used in conjunction with Tg mice expressing beta-galactosidase (βgal) as retinal neo-self antigen and βgal-specific TCR Tg mice (BG2). Retinal T cell responses were assayed by flow cytometry and retinal autoimmune disease assessed by histological examination.ResultsLocal depletion of the Tregs enhanced actively induced experimental autoimmune uveoretinitis to the highly expressed retinal self-antigen IRBP in FDG mice and spontaneous autoimmunity in βgal-FDG-BG2 mice, but not in mice lacking autoreactive T cells or their target antigen in the retina. The presence of retinal βgal downregulated the generation of antigen-specific Teffs and pTregs within the retina in response to local βgal challenge. Retinal DC depletion prevented generation of Tregs and Teffs within retina after βgal injection. Microglia remaining after DC depletion did not make up for loss of DC-dependent antigen presentation.ConclusionsOur results suggest that local retinal Tregs protect against spontaneous organ-specific autoimmunity and that T cell responses within the retina require the presence of local DC.
Highlights
We previously reported that the peripheral regulatory T cells generated ‘on-demand’ in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs)
Beta-galactosidase-specific regulatory T cells are made in the periphery and modulate CD4+ T cell responses to βgal The lack of βgal expression in the thymus of βgal mice by reverse transcription PCR (RT-PCR) [50] and X-gal staining (Figure 1A) suggested that most βgal-specific Tregs are likely peripherally derived Treg (pTreg)
Βgal-specific, FoxP3+ pTregs could be generated in vivo, we asked if Tregs induced by administration of soluble Ag [52] and transferred into BG2 mice could suppress the delayed-type hypersensitive (DTH) response of βgal-specific CD4+ BG2 T cells
Summary
We previously reported that the peripheral regulatory T cells (pTregs) generated ‘on-demand’ in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Analysis of pTregs for their overall contribution to the Treg population, as well as their exact sites of generation and action (within a specific tissue or nearby secondary lymphoid tissue), is a matter of ongoing investigation Limiting these studies is the lack of unique marker(s) distinguishing tTregs and pTregs. It has been difficult to determine if these tissue Tregs resulted from immigration of tTreg or were pTregs generated in secondary lymphoid tissue
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