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 ofHdac1(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 theRosa26locus in HDAC1cKOCD4+T cells to mimic selective inhibition of HDAC1 enzymatic activityin vivo. Mice expressing wildtype HDAC1 in HDAC1cKOCD4+T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1Onmice, HDAC1Offmice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1OffCD4+T cells in the CNS displayed a severe reduction of IFNγ, IL-17A and TNFα proinflammatory cytokine expression, andin vivoactivated HDAC1OffCD4+T cells downregulated gene sets associated with T cell activation, cytokine expression and cell migration. This indicates impaired effector functions of HDAC1OffCD4+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.HighlightsSuccessful generation of a novel mouse model that expresses enzymatic-inactive HDAC1 to mimic HDAC1 inhibitor treatmentin vivo.Mice expressing enzymatically inactive HDAC1 instead of WT HDAC1 in T cells do not develop EAE and display diminished leukocyte CNS infiltration.In vivoactivated CD4+T cells expressing enzymatic inactive HDAC1 downregulate pathways important for T cell activation, cytokine expression and cell migration.Demonstrate the proof-of-principle that targeting the enzymatic activity of HDAC1 is a promising treatment strategy for autoimmune diseases.

HDAC1 acts as tumor suppressor in ALK-positive anaplastic large-cell lymphoma: Implications for HDAC inhibitor therapy

“…Thus, besides its enzymatic function, HDAC1 is also required for complex formation. To disentangle its catalytic and scaffolding functions, we made use of dHdac1 knock-in (KI) mice that express a catalytically inactive (dead) HDAC1 protein, which can still integrate into corepressor complexes 24,25 . This model reflects the effects of HDACi, which are small molecules binding to the catalytic pocket of HDAC proteins 45 , more closely.…”

“…Cd4 -NPM-ALK transgenic mice 21 , mice carrying loxP-flanked Hdac1 22 or Hdac2 22 and Cd4 -Cre mice 23 were crossed to obtain NPM-ALK Hdac1 KO and NPM-ALK Hdac2 KO mice. Similarly, NPM-ALK Hdac1 KO mice were crossed with mice with a Rosa26 knock-in (KI) construct containing the Hdac1 gene with a His141→Ala point mutation, which results in expression of catalytically inactive HDAC1 24,25 . Genotyping of mice is described in the Supplementary Methods.…”