6533b7d0fe1ef96bd125af9d

RESEARCH PRODUCT

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

Liisa AndersenIlgiz A. MufazalovMichael BonelliTeresa PreglejVictoria SaferdingKiyoshi HiraharaMichael SchusterAlexandra Franziska GülichThomas PenzNicole BoucheronChristian SeiserAri WaismanChristoph BockPatrick MatthiasWilfried EllmeierGünter SteinerLisa GöschlPatricia HammingerLena Müller

subject

0301 basic medicineReceptors CCR6Encephalomyelitis Autoimmune ExperimentalMultiple SclerosisReceptors CCR4T cellImmunologyCCR4Histone Deacetylase 1C-C chemokine receptor type 6Biologymedicine.disease_causeAutoimmunity03 medical and health sciencesChemokine receptorMice0302 clinical medicineCell MovementmedicineImmunology and AllergyAnimalsHumansCells CulturedMice KnockoutChimeraMultiple sclerosisExperimental autoimmune encephalomyelitisGene targetingmedicine.diseaseMolecular biologyDisease Models Animal030104 developmental biologymedicine.anatomical_structureSTAT1 Transcription FactorCancer researchTh17 Cells030215 immunology

description

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.

10.1016/j.jaut.2017.09.008https://pubmed.ncbi.nlm.nih.gov/28964722