T cell receptor (TCR) stimulation of naive CD8+ T cells initiates reprogramming ofcis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naive cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 promoted accessibility to memory CTL-specificcis-regulatory regions before the first cell division and was essential for memory CTL differentiation. Runx3 was specifically required for accessibility to regions highly enriched with IRF, bZIP and Prdm1-like TF motifs, upregulation of TFs Irf4 and Blimp1, and activation of fundamental CTL attributes in early effector and memory precursor cells. Runx3 ensured that nascent CTLs differentiated into memory CTLs by preventing high expression of the TF T-bet, slowing effector cell proliferation, and repressing terminal CTL differentiation. Runx3 overexpression enhanced memory CTL differentiation during iterative infections. Thus, Runx3 governs chromatin accessibility during TCR stimulation and enforces the memory CTL developmental program.In Brief
Chromatin accessibility in naive CD8+ T cells is globally reprogrammed during infection. Wang et al. show that the transcription factor Runx3 programs chromatin accessibility during stimulation of naive CD8+ T cells, which establishes early transcriptional circuits that drive differentiation of nascent cytotoxic T lymphocytes (CTLs), and also represses terminal differentiation to ensure that they develop into long-lived memory CTLs.