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Darren J Lee, Andrew W Taylor; Melanocortin Receptor Stimulation Induces CD4+CD25+NRP-1- Treg cells to Suppress Experimental Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3574.
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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 through the adenosine 2A receptor (A2Ar) by melanocortin 5 receptor expressing (MC5r) regulatory post-EAU APC. The ligand for MC5r, α-melanocyte stimulating hormone (α-MSH), induces a regulatory APC that promotes Treg cell activation. Neuropilin-1 (NRP-1) has been reported to distinguish between inducible (iTreg) or natural (nTreg) nTreg cells. It is not known whether the post-EAU Treg cells are iTreg or nTreg cells. This work shows that the α-MSH induced regulatory APC promotes CD4+CD25+ Treg cells that are NRP-1-.
C57BL/6 (WT) and A2Ar(-/-) mice were immunized with IRBPp 1-20 in CFA to induce EAU. Spleen T cells from WT and A2Ar(-/-) post-EAU mice were re-stimulated with IRBP for 48 hours, stained for CD4, CD25, and NRP-1, analyzed by flow cytometry, and sorted T cells were transferred into recipient EAU mice. WT APC from unimmunized mice were collected from the spleen, treated with α-MSH for 48 hours, washed, and used to activate IRBP-specific primed T cells. These T cells were stained for the above markers and assessed for regulatory activity by adoptive transfer of sorted NRP-1- and NRP-1+CD4+CD25- T cells into mice immunized for EAU.
EAU duration and severity was nearly identical in WT and A2Ar(-/-) mice; however, post-EAU A2Ar(-/-) mice lacked regulatory immunity in their spleens. Also, they had significantly less NRP-1- T cells in their spleens compared to T cells from WT post-EAU mice. Transfer of sorted NRP-1- T cells activated by α-MSH treated APC suppressed EAU in recipient mice. In contrast, mice that received sorted WT NRP-1+ T cells, A2Ar(-/-) NRP-1+, or A2Ar(-/-) NRP-1- T cells showed a similar course of disease compared to untreated mice.
The A2Ar-dependent post-EAU Treg cell is CD4+ CD25+ NRP-1-. Therefore, as EAU resolves the melanocortin-mediated regulatory APC activates a protective ocular autoantigen-specific iTreg cell.
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