Martin W LaFleur, Jasmin M D'Andrea, Dillon G Patterson, Ivy S L Streeter, Matthew A Coxe, Jossef F Osborn, Lauren E Milling, Qin Tjokrosurjo, Jacob E Gillis, Thao H Nguyen, Marc A Schwartz, Nir Hacohen, John G Doench, Arlene H Sharpe
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引用次数: 0
摘要
CD8+ T细胞在应对急性病毒感染时会分化成两个亚群:记忆前体效应细胞(MPECs)和短效效应细胞(SLECs)。记忆前体效应细胞(MPECs)和短效效应细胞(SLECs)在表观遗传学上是不同的;然而,这些亚群形成所需的表观遗传学调节因子大多不为人知。在这项研究中,我们利用急性淋巴细胞性脉络膜炎病毒阿姆斯特朗感染模型,在小鼠天真 CD8+ T 细胞中进行了体内 CRISPR 筛选,以确定 MPEC 和 SLEC 形成所需的表观遗传调节因子。我们发现依赖 ATP 的染色质重塑因子 CHD7(染色质域-螺旋酶 DNA 结合蛋白 7)是 SLEC 形成的正调控因子,因为敲除(KO)Chd7 会减少 SLEC 的数量。与此相反,在病原体清除后,Chd7 的基因敲除会增加中心记忆 T 细胞的形成,但在再次挑战后,记忆细胞的扩增会减弱。这些发现确立了CHD7是SLEC的新型正调控因子和中枢记忆T细胞形成的负调控因子。
In Vivo CRISPR Screening Reveals CHD7 as a Positive Regulator of Short-lived Effector Cells.
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.
期刊介绍:
The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)