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Cell. 2019 Jan 10;176(1-2):348-360.e12. doi: 10.1016/j.cell.2018.11.045. Epub 2018 Dec 27.

Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
Merck KGaA, Darmstadt Germany.
3
Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: eugene.oltz@osumc.edu.
5
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: mcolonna@wustl.edu.

Abstract

Natural killer (NK) cells develop from common progenitors but diverge into distinct subsets, which differ in cytokine production, cytotoxicity, homing, and memory traits. Given their promise in adoptive cell therapies for cancer, a deeper understanding of regulatory modules controlling clinically beneficial NK phenotypes is of high priority. We report integrated "-omics" analysis of human NK subsets, which revealed super-enhancers associated with gene cohorts that may coordinate NK functions and localization. A transcription factor-based regulatory scheme also emerged, which is evolutionarily conserved and shared by innate and adaptive lymphocytes. For both NK and T lineages, a TCF1-LEF1-MYC axis dominated the regulatory landscape of long-lived, proliferative subsets that traffic to lymph nodes. In contrast, effector populations circulating between blood and peripheral tissues shared a PRDM1-dominant landscape. This resource defines transcriptional modules, regulated by feedback loops, which may be leveraged to enhance phenotypes for NK cell-based therapies.

PMID:
30595449
PMCID:
PMC6329660
[Available on 2020-01-10]
DOI:
10.1016/j.cell.2018.11.045

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