美国圣犹达儿童研究医院Hongbo Chi团队近期取得重要工作进展，他们通过CRISPR筛选揭示了影响肠组织驻留记忆CD8⁺ T细胞形成的营养依赖性溶酶体和线粒体节点。相关研究成果2024年10月14日在线发表于《免疫》杂志上。

据介绍，营养可用性和细胞器生物学指导组织稳态和细胞命运，但这些过程如何协调组织免疫仍然知之甚少。

通过使用体内CRISPR-Cas9筛选，研究人员发现了塑造CD8⁺组织驻留记忆T（T_RM）细胞发育的细胞器信号传导和代谢过程。T_RM细胞依赖于线粒体翻译和呼吸。相反，三个营养依赖性溶酶体信号节点（Flcn、Ragulator和Rag GTP酶）抑制了肠道T_RM细胞的形成。耗尽这些分子或氨基酸会激活转录因子Tfeb，从而将营养胁迫与T_RM编程联系起来。

此外，Flcn缺乏促进了小肠中T_RM细胞的保护性反应。从机制上讲，Flcn-Tfeb轴抑制了视黄酸诱导的CCR9表达，以促进迁移和转化生长因子β（TGF-β）介导的谱系分化程序。遗传相互作用筛选显示，线粒体蛋白Mrpl52能够促进早期TRM细胞形成，而Acss1在Flcn缺乏相关的溶酶体失调下控制T_RM细胞发育。因此，营养物质、细胞器信号和代谢适应之间的相互作用决定了组织免疫。

附：英文原文

Title: CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation

Author: Jana L. Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M. Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil KC, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P. Connelly, Shondra M. Pruett-Miller, Miguel Reina-Campos, Ananda W. Goldrath, Yasmine Belkaid, Hongbo Chi

Issue&Volume: 2024-10-14

Abstract: Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes—Flcn, Ragulator, and Rag GTPases—inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.

DOI: 10.1016/j.immuni.2024.09.013

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00457-6