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Darren Lee, Andrew Taylor; A Functional Link Between the Melanocortin and Adenosinergic Pathways in the Expression of Protective Regulatory Immunity in the Post-EAU Spleen. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3667.
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© ARVO (1962-2015); The Authors (2016-present)
IRBP-specific regulatory immunity is found in the spleen of mice that have recovered from experimental autoimmune uveoretinitis (EAU). This post-EAU regulatory immunity requires post-EAU Treg cells to be activated by regulatory MC5r+Ly-6G+CD11b+ post-EAU APC. Since stimulation of the adenosine 2A receptor (A2Ar) on T cells triggers anti-inflammatory and regulatory activity, and there may be a link between the melanocortin and adenosine pathways we examined the role of A2Ar in the induction of regulatory immunity in the post-EAU spleen.
Primary spleen APC were treated with α−MSH, stained for CD11b, Ly-6G, ectoenzymes CD39 and CD73, and analyzed by flow cytometry. C57BL/6 (WT) and A2Ar(-/-) mice were immunized with IRBPp 1-20 in CFA to induce EAU. WT EAU mice were treated during EAU with 3 systemic injections of the A2Ar agonist, CGS21680 (CGS). The fundus was monitored until resolution, and reactivated post-EAU T cells were stained for FoxP3. At resolution of EAU, spleen APC and T cells were collected from A2Ar(-/-) or WT mice. WT APC were used to restimulate A2Ar(-/-) T cells or A2Ar(-/-) APC restimulated Treg cells and transferred to recipient EAU mice.
CD39 and CD73 expression was modestly higher on Ly-6G+ APC compared to Ly-6G- APC. α-MSH treated Ly-6G+ APC showed a dramatic upregulation of CD73 not observed on Ly-6G- APC; CD39 expression increased slightly on Ly-6G+ APC, whereas, Ly-6G- showed decreased CD39 expression. CGS treatment accelerated the resolution of EAU and suppressed effector T cells in the spleen. EAU duration and severity was nearly identical in WT and A2Ar(-/-) mice. However, post-EAU A2Ar(-/-) mice lacked regulatory immunity in the spleen and had significantly less CD25+ FoxP3+ T cells. APC from A2Ar(-/-) mice activated post-EAU Treg cells to suppress EAU in recipient mice. In contrast, mice that received post-EAU APC and post-EAU A2Ar(-/-) T cells showed a similar course of disease compared to untreated mice.
T cell expression of A2Ar is required for the regulatory Ly-6G+ CD11b+ APC to activate Treg cells. This report identified a link between the melanocortin and adenosinergic pathways through MC5r stimulation on the Ly-6G+ APC to augment adenosine generation to promote Treg cell induction through A2Ar.
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