Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

Abstract

Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion of Hdac1 (HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity, which could be achieved therapeutically by HDAC1 inhibitor treatment, is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from the Rosa26 locus in HDAC1cKO CD4+ T cells to mimic selective inhibition of HDAC1 enzymatic activity in vivo. Mice expressing wildtype HDAC1 in HDAC1cKO CD4+ T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1On mice, HDAC1Off mice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1Off CD4+ T cells in the CNS displayed a severe reduction of IFN{gamma}, IL-17A and TNF proinflammatory cytokine expression, and in vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, cytokine expression and cell migration. This indicates impaired effector functions of HDAC1Off CD4+ T cells. Taken together, our study demonstrates that the inhibition of the catalytic activity of HDAC1 in T cells is sufficient to achieve a clinical benefit in EAE disease development. This raises the translational perspective of pharmacological HDAC1 inhibition for treating human T cell-mediated autoimmune diseases. HighlightsO_LISuccessful generation of a novel mouse model that expresses enzymatic-inactive HDAC1 to mimic HDAC1 inhibitor treatment in vivo. C_LIO_LIMice expressing enzymatically inactive HDAC1 instead of WT HDAC1 in T cells do not develop EAE and display diminished leukocyte CNS infiltration. C_LIO_LIIn vivo activated CD4+ T cells expressing enzymatic inactive HDAC1 downregulate pathways important for T cell activation, cytokine expression and cell migration. C_LIO_LIDemonstrate the proof-of-principle that targeting the enzymatic activity of HDAC1 is a promising treatment strategy for autoimmune diseases. C_LI