A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis

J Autoimmun. 2018 Jan;86:51-61. doi: 10.1016/j.jaut.2017.09.008. Epub 2017 Sep 28.

Abstract

Multiple sclerosis (MS) is a human neurodegenerative disease characterized by the invasion of autoreactive T cells from the periphery into the CNS. Application of pan-histone deacetylase inhibitors (HDACi) ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model for MS, suggesting that HDACi might be a potential therapeutic strategy for MS. However, the function of individual HDAC members in the pathogenesis of EAE is not known. In this study we report that mice with a T cell-specific deletion of HDAC1 (using the Cd4-Cre deleter strain; HDAC1-cKO) were completely resistant to EAE despite the ability of HDAC1cKO CD4+ T cells to differentiate into Th17 cells. RNA sequencing revealed STAT1 as a prominent upstream regulator of differentially expressed genes in activated HDAC1-cKO CD4+ T cells and this was accompanied by a strong increase in phosphorylated STAT1 (pSTAT1). This suggests that HDAC1 controls STAT1 activity in activated CD4+ T cells. Increased pSTAT1 levels correlated with a reduced expression of the chemokine receptors Ccr4 and Ccr6, which are important for the migration of T cells into the CNS. Finally, EAE susceptibility was restored in WT:HDAC1-cKO mixed BM chimeric mice, indicating a cell-autonomous defect. Our data demonstrate a novel pathophysiological role for HDAC1 in EAE and provide evidence that selective inhibition of HDAC1 might be a promising strategy for the treatment of MS.

Keywords: Autoimmunity; CD4(+) T cells; Experimental autoimmune encephalomyelitis; Gene targeting; Histone deacetylases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Chimera
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / metabolism*
  • Receptors, CCR4 / metabolism
  • Receptors, CCR6 / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Th17 Cells / physiology*

Substances

  • CCR6 protein, mouse
  • Ccr4 protein, mouse
  • Receptors, CCR4
  • Receptors, CCR6
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Hdac1 protein, mouse
  • Histone Deacetylase 1