CUT&RUN for “HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection”
CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study un-covers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection. Overall design: 10 WT and mice with T cell-specific HDAC1-deficiency (all age-matched) were infected with LCMV cl13 samples and their spleens were isolated on d8 post infection. T cells were enriched and cells were sorted for viability, TCRb, CD8, CD44, PD-1 and either Ly108 (early-TexProg) or Tim3 (early-non-TexProg). Nuclei from both early-TexProg and early-non-TexProg cells were isolated and CUT&RUN was performed for the following targets: HDAC1, H3K27ac, Runx3, H3K27me3, IgG.