Abstract
The ocular microenvironment uses a poorly defined mela5 receptor (MC5r)-dependent pathway to recover immune tolerance following intraocular inflammation. This dependency is seen in experimental autoimmune uveoretinitis (EAU), a mouse model of endogenous human autoimmune uveitis, with the emergence of autoantigen-specific regulatory immunity in the spleen that protects the mice from recurrence of EAU. In this study, we found that the MC5r-dependent regulatory immunity increased CD11b(+)F4/80(+)Ly-6C(low)Ly-6G(+)CD39(+)CD73(+) APCs in the spleen of post-EAU mice. These MC5r-dependent APCs require adenosine 2A receptor expression on T cells to activate EAU-suppressing CD25(+)CD4(+)Foxp3(+) regulatory T cells. Therefore, in the recovery from autoimmune disease, the ocular microenvironment induces tolerance through a melanocortin-mediated expansion of Ly-6G(+) regulatory APCs in the spleen that use the adenosinergic pathway to promote activation of autoantigen-specific regulatory T cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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5'-Nucleotidase / metabolism
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Animals
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Antigens, CD / metabolism
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Antigens, Ly / metabolism
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Apyrase / metabolism
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Autoantigens / immunology
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Autoimmune Diseases
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CD11b Antigen / metabolism
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CD4 Antigens / metabolism
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Disease Models, Animal
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Eye / immunology
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Eye Proteins / immunology
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Forkhead Transcription Factors / metabolism
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Inflammation / immunology
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Interleukin-2 Receptor alpha Subunit / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Receptor, Adenosine A2A / metabolism*
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Receptors, Melanocortin / genetics
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Receptors, Melanocortin / metabolism*
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Retinol-Binding Proteins / immunology
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Self Tolerance / immunology*
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Spleen / immunology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Uveitis / immunology*
Substances
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Antigens, CD
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Antigens, Ly
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Autoantigens
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CD11b Antigen
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CD4 Antigens
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Eye Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2 Receptor alpha Subunit
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Ly6 protein, mouse
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Receptor, Adenosine A2A
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Receptors, Melanocortin
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Retinol-Binding Proteins
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interstitial retinol-binding protein
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melanocortin 5 receptor
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5'-Nucleotidase
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Apyrase
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CD39 antigen