Targeting HDAC1 enzymatic activity in T cells protects against experimental autoimmune encephalomyelitis
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 and thus mimicking 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?, IL-17A and TNFa proinflammatory cytokine expression. In vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, inflammatory response and cell migration, indicating impaired effector functions of HDAC1Off CD4+ T cells. Thus, our study demonstrates that the inhibition of the catalytic activity of HDAC1 is sufficient to achieve a clinical benefit in EAE disease development. This raises the exciting translational perspective that targeting HDAC1 enzymatic activity is a promising therapeutic strategy in treating human T cell-mediated autoimmune diseases. Overall design: Cells from draining (popliteal) lymph nodes were isolated and RNA was extracted from single cell suspension. Two mice were pooled for one biological replicate and three biological replicates were generated for each genotype (group). One WT group and one catalalytically inactive group were included.