By mapping regions of hyper-accessible chromatin following TCR stimulation and identifying transcription factor motifs in the remodeled regions, Wang et al. found that in TCR-stimulated naive CD8+ T cells, chromatin accessibility reprogramming is mediated by the transcription factor Runx3. In a series of gain- and loss-of-function experiments, they showed that Runx3 drives differentiation of cytotoxic T lymphocytes, but represses terminal differentiation, and was essential in the development of memory precursor CTLs, in part by preventing high expression of T-bet and by slowing proliferation.

T cell receptor (TCR) stimulation of naive CD8(+) T cells initiates reprogramming of cis-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-specific cis-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.

Author Info: (1) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (2) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL

Author Info: (1) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (2) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (3) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (4) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (5) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. (6) Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. (7) Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. (8) Division of Vaccine Discovery, The La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA; Division of Infectious Diseases, Department of Medicine, UCSD School of Medicine, La Jolla, CA, USA. (9) Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. (10) Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. Electronic address: mpipkin@scripps.edu.

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