KDM6B-dependent chromatin remodelling underpins effective virus-specific CD8⁺T cell differentiation

Naive CD8⁺T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here we profiled genome-wide changes in chromatin accessibility, gene transcription and the deposition of a key chromatin modification (H3K27me3) early after naive CD8⁺T cell activation. Rapid upregulation of the histone demethylase, KDM6B, prior to first cell division was required for initiating H3K27me3 removal at genes essential for subsequent T cell differentiation and proliferation. Inhibition of KDM6B-dependent H3K27me3 demethylation limited the magnitude of an effective primary virus-specific CD8⁺T cell response and the formation of memory CD8⁺T cell populations. Accordingly, we define the early spatio-temporal events underpinning early lineage-specific epigenetic reprogramming that is necessary for autonomous CD8⁺T cell proliferation and differentiation.