Abstract
Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and exhibit important functional properties in antimicrobial and antitumoral responses. Our previous work indicated that the enhancer of zeste homolog 2 (Ezh2) is a negative regulator of early NK cell differentiation and function through trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK cells and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on the transcriptional signature during NK cell maturation. Conditional deletion of Ezh2 in NK cells resulted in a maturation trajectory toward NK cell arrest in CD11b SP stage 5, which was clustered with genes related to the activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating AP-1 family gene expression independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis in altering the NK cell maturation trajectory and NK cell-mediated cytotoxicity.
Highlights
Natural killer (NK) cells are lymphocytes belonging to innate immunity with effector functions, including roles as cytolytic effectors and potent producers of cytokines [1,2,3]
We previously reported that deletion or inhibition of enhancer of zeste homolog 2 (Ezh2) in hematopoietic stem and progenitor cells (HSPCs) enhanced NK cell commitment and cytotoxicity against tumor cells [17]
Our previous research showed that Ezh2 is a negative regulator of NK cell differentiation and function [17]
Summary
Natural killer (NK) cells are lymphocytes belonging to innate immunity with effector functions, including roles as cytolytic effectors and potent producers of cytokines [1,2,3]. After acquiring NK1.1 and CD49b surface expression, murine NK cells can further develop to maturity [4, 5]. NK cell maturation in vivo follows the pathway CD11blowCD27high (CD27 single positive, CD27 SP) ! CD11bhighCD27low (CD11b single positive, CD11b SP) [6]. Klrg is a marker of terminal maturation acquired by NK cells [7, 8]. Scott et al found that Klrg is a C-type lectin-like inhibitory receptor with an immune receptor tyrosine-based inhibitory motif in its cytoplasmic domain during the activation of mouse NK cells [9].
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