ATAC-seq 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: Naïve WT and HDAC1-cKO P14 T cells (CD90.2+) were intravenously transferred into CD90.1+ congenic mice, which were infected with the LCMV Cl13 strain one day after the transfer. Eight days later, splenocytes of 4-5 female mice, where either WT or HDAC1-cKO cells had been transfered, were isolated, and early-Texprog (CD90.2+CD8a+Tim3-Ly108+) as well as non-early Texprog (CD90.2+CD8a+Tim3+Ly108-) cells were sorted into 1x PBS. After spinning cells down at 500g for 5min at 4°C, the cell pellets were resuspended in tagmentation-mix and incubated for 30min at 37°C with shaking (300rpm). The reaction was stopped by incubating the samples on ice. For DNA isolation, the MinElute PCR Purification Kit (Qiagen) was used according to the manufacturer's instructions and eluted into 12 µl of elution buffer.