UTX constrains antiviral CD8+ T cell responses during chronic virus infection

Persistent virus infections can cause pathogenesis that is debilitating or lethal. During these infections, virus-specific T cells fail to protect due to weakened antiviral activity or failure to persist. These outcomes are governed epigenetically, though it is unknown which enzymes contribute to T cell loss or impaired function over time. Here, we show that T cell receptor-stimulated CD8+ T cells increase their expression of UTX (Ubiquitously transcribed Tetratricopeptide repeat, X-chromosome), an enzyme involved in demethylating histone-3 lysine-27 (H3K27), and reduce genome-wide H3K27-me3. UTX limits the frequency and durability of virus-specific CD8+ T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice by promoting inhibitory receptor expression and apoptosis. UTX also increases effector gene expression to improve CTL-mediated protection, a process corresponding to reduced H3K27me3 at effector gene bodies. Thus, UTX guides gene expression patterns in CD8+ T cells, promoting antiviral activity while reducing CD8+ T cell durability. Overall design: RNA-seq, H3K27me3 CUT&RUN, and UTX CUT&Tag comparision of mouse WT P14 CD8+ T cells to Utx-/- P14 CD8+ T cells following adoptive transfer and LCMV-A22 infection. For RNA-seq, there were 3 WT replicates and 4 Utx -/- replicates 21 days post LCMV-A22 infection. For H3K27me3 CUT&RUN, there were 4 replicates for each group 15 days post LCMV-A22 infection. For UTX CUT&Tag, there were 4 WT replicates and 2 Utx -/- replicates 15 days post LCMV-A22 infection as well as 2 WT replicates prior to infection (day 0).