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Resident memory T cells: Runx and hide

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Science Immunology  05 Jan 2018:
Vol. 3, Issue 19, eaar5172
DOI: 10.1126/sciimmunol.aar5172

Abstract

The transcription factor Runx3 enhances the differentiation and survival of CD8+ resident memory T cells; enhancing Runx3 expression in responding T cells could lead to better therapies for infection and cancer.

Resident memory T cells (TRM) express a distinct set of genes, live long-term in peripheral tissues, and rapidly protect against known pathogens. The cells that give rise to TRM and the signals that control their differentiation have remained a mystery. Recent studies by Milner et al. identify the transcription factor Runx3 as a master regulator for inducing and maintaining CD8+ TRM. The authors found that by day seven after infection with lymphocytic choriomeningitis virus (LCMV), murine CD8+ T cells in peripheral tissues already expressed a distinct gene expression pattern. By combining transcriptional profiling, chromatin accessibility analyses, PageRank analyses, and pooled in vivo RNA interference assays, the authors identified Runx3 as a key regulator of the TRM phenotype. Deletion of Runx3 in CD8+ T cells reduced formation and maintenance of TRM in multiple tissues after LCMV infection, and Runx3 overexpression increased TRM numbers. Runx3 appeared to function by reducing TRM apoptosis; it did not affect T cell proliferation or entry into tissues. Computational integration of gene expression of CD8+ intraepithelial lymphocytes across multiple tissues showed that Runx3 expression correlated closely with the enhanced expression of tissue resident signature genes and reduced expression of genes involved in tissue egress and recirculation. In chromatin immunoprecipitation experiments, Runx3 bound preferentially to the promoters of both core tissue residency and recirculating genes, suggesting that it is a key regulator of the resident versus recirculating phenotype. In a melanoma model, T cells expressing high levels of Runx3 were more effective in controlling tumor growth. Last, the authors used single-cell RNA sequencing of CD8+ T cells from human melanomas to show that higher Runx3 levels were correlated with expression of resident memory associated genes. These studies are the first to identify Runx3 as a master regulatory switch that supports the differentiation and retention of CD8+ TRM. Increasing Runx3 expression in T cells could lead to enhanced TRM generation and better immune responses against infections and cancers.

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