体内 CRISPR 筛选揭示 CHD7 是短命效应细胞的正调控因子。
In Vivo CRISPR Screening Reveals CHD7 as a Positive Regulator of Short-lived Effector Cells.
机构信息
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA.
Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
出版信息
J Immunol. 2024 Nov 15;213(10):1528-1541. doi: 10.4049/jimmunol.2400213.
CD8+ T cells differentiate into two subpopulations in response to acute viral infection: memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). MPECs and SLECs are epigenetically distinct; however, the epigenetic regulators required for formation of these subpopulations are mostly unknown. In this study, we performed an in vivo CRISPR screen in murine naive CD8+ T cells to identify the epigenetic regulators required for MPEC and SLEC formation, using the acute lymphocytic choriomeningitis virus Armstrong infection model. We identified the ATP-dependent chromatin remodeler CHD7 (chromodomain-helicase DNA-binding protein 7) as a positive regulator of SLEC formation, as knockout (KO) of Chd7 reduced SLECs numerically. In contrast, KO of Chd7 increased the formation of central memory T cells following pathogen clearance yet attenuated memory cell expansion following a rechallenge. These findings establish CHD7 as a novel positive regulator of SLEC and a negative regulator of central memory T cell formation.
CD8+ T 细胞在急性病毒感染后分化为两个亚群：记忆前体效应细胞（MPECs）和短寿命效应细胞（SLECs）。MPECs 和 SLECs 在表观遗传学上是不同的；然而，形成这些亚群所需的表观遗传调节剂大多是未知的。在这项研究中，我们使用急性淋巴细胞性脉络丛脑膜炎病毒 Armstrong 感染模型，在小鼠幼稚 CD8+ T 细胞中进行了体内 CRISPR 筛选，以鉴定形成 MPEC 和 SLEC 所需的表观遗传调节剂。我们发现 ATP 依赖的染色质重塑酶 CHD7（染色质结构域螺旋酶 DNA 结合蛋白 7）是 SLEC 形成的正调节剂，因为 Chd7 的敲除（KO）在数量上减少了 SLECs。相比之下，Chd7 的 KO 在清除病原体后增加了中央记忆 T 细胞的形成，但在再次挑战后减弱了记忆细胞的扩增。这些发现确立了 CHD7 作为 SLEC 的新型正调节剂和中央记忆 T 细胞形成的负调节剂。
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