Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice

J Immunol. 2013 Oct 15;191(8):4103-11. doi: 10.4049/jimmunol.1300182. Epub 2013 Sep 16.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • 5'-Nucleotidase / metabolism
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Ly / metabolism
  • Apyrase / metabolism
  • Autoantigens / immunology
  • Autoimmune Diseases
  • CD11b Antigen / metabolism
  • CD4 Antigens / metabolism
  • Disease Models, Animal
  • Eye / immunology
  • Eye Proteins / immunology
  • Forkhead Transcription Factors / metabolism
  • Inflammation / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Adenosine A2A / metabolism*
  • Receptors, Melanocortin / genetics
  • Receptors, Melanocortin / metabolism*
  • Retinol-Binding Proteins / immunology
  • Self Tolerance / immunology*
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Uveitis / immunology*

Substances

  • Antigens, CD
  • Antigens, Ly
  • Autoantigens
  • CD11b Antigen
  • CD4 Antigens
  • Eye Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Ly6 protein, mouse
  • Receptor, Adenosine A2A
  • Receptors, Melanocortin
  • Retinol-Binding Proteins
  • interstitial retinol-binding protein
  • melanocortin 5 receptor
  • 5'-Nucleotidase
  • Apyrase
  • CD39 antigen