MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis

J Autoimmun. 2014 Sep:53:95-104. doi: 10.1016/j.jaut.2014.05.006. Epub 2014 Jun 14.

Abstract

Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for TH17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed TH17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE.

Keywords: EAE; Epigenetic; MBD2; Methylation; T(H)17; T-bet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Epigenesis, Genetic / genetics
  • Epigenesis, Genetic / immunology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Peptide Fragments / toxicity
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology*
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology*

Substances

  • DNA-Binding Proteins
  • Hlx protein, mouse
  • Homeodomain Proteins
  • Mbd2 protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • myelin oligodendrocyte glycoprotein (35-55)