美国加州大学洛杉矶分校Timothy E. O’Sullivan研究组近日取得一项新成果。经过不懈努力，他们发现MEF2C通过控制脂质代谢调节自然杀伤（NK）细胞的效应功能。这一研究成果发表在2024年4月8日出版的国际学术期刊《自然-免疫学》上。

研究人员利用非病毒CRISPR-Cas9基因敲除筛选技术，靶向编码人NK细胞发育过程中31个表达不同转录因子的基因。研究发现肌细胞增强因子2C(MEF2C)是人NK细胞体内功能的主调节因子。缺失MEF2C的患者和小鼠具有NK细胞发育和效应功能缺陷，对病毒感染的易感性增加。

从机理上讲，白细胞介素（IL）-2和IL-15通过调节甾醇调节元件结合蛋白（SREBP）途径调控脂质含量的增加，这一过程需要MEF2C。补充油酸可恢复MEF2C缺陷表型和MEF2C单倍体缺陷表型患者，NK细胞的细胞毒性功能。因此，MEF2C通过调节SREBP介导脂质代谢，其是NK细胞抗病毒免疫的关键协调因子。

研究人员表示，NK细胞是抵御病毒感染的第一道关键防线。一小部分转录因子的罕见突变会导致人NK细胞数量和功能下降，从而增加对病毒感染的易感性。然而，人们对调控人成熟NK细胞功能的特定转录因子的了解还十分有限。

附：英文原文

Title: MEF2C regulates NK cell effector functions through control of lipid metabolism

Author: Li, Joey H., Zhou, Adalia, Lee, Cassidy D., Shah, Siya N., Ji, Jeong Hyun, Senthilkumar, Vignesh, Padilla, Eddie T., Ball, Andra B., Feng, Qinyan, Bustillos, Christian G., Riggan, Luke, Greige, Alain, Divakaruni, Ajit S., Annese, Fran, Cooley-Coleman, Jessica, Skinner, Steven A., Cowan, Christopher W., OSullivan, Timothy E.

Issue&Volume: 2024-04-08

Abstract: Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR–Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.

DOI: 10.1038/s41590-024-01811-2

Source: https://www.nature.com/articles/s41590-024-01811-2