Abstract
Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1+FoxP3+ Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.
Highlights
Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen
Since it has been previously demonstrated in vitro that ocular autoantigen-specific Treg cells suppress interphotoreceptor retinoid binding protein (IRBP)-specific inflammatory T cells in a Programmed death receptor 1 (PD-1)/ PD-L1 dependent manner[15], we asked if these same Treg cells require the PD-1/PD-L1 pathway for functional suppression of EAU in vivo
We show that the PD-1+CD25+CD4+ Treg cells require PD-1 stimulation to suppress EAU and that these Treg cells do not function to induce suppressor activity in antigen presenting cells (APC) through the PD-1 pathway
Summary
Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. The post-EAU regulatory immunity that provides resistance to EAU requires expression of the adenosine 2 A receptor (A2Ar) on T cells, and suppressor APC that express the melancortin 5 receptor (MC5r)[12,14,15]. The post-EAU suppressor APC activates Treg cells that express PD-1 and PD-L1 and suppress effector cytokines in a PD-1/PD-L1 dependent manner[15]. It has not been demonstrated if these post-EAU Tregs require the PD-1/PD-L1 pathway to functionally suppress EAU.
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