Sugiura Ayaka, Beier Katherine L, Chi Channing, Heintzman Darren R, Ye Xiang, Wolf Melissa M, Patterson Andrew R, Cephus Jacqueline-Yvonne, Hong Hanna S, Lyssiotis Costas A, Newcomb Dawn C, Rathmell Jeffrey C
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
bioRxiv. 2023 Sep 13:2023.09.13.557496. doi: 10.1101/2023.09.13.557496.
Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4 T cell subset requirements for specific AA remains uncertain. Here we tested CD4 T cell AA demands with and multiple CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time and lung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4 T cells on AA transporters may guide selective immunotherapies.
氨基酸（AA）摄取对于T细胞代谢和功能至关重要，但组织部位和炎症如何影响CD4 T细胞亚群对特定氨基酸的需求仍不确定。在这里，我们通过多个CRISPR筛选测试了CD4 T细胞的氨基酸需求，并确定了对氨基酸转运体SLC38A1（SNAT1）的亚群和组织特异性依赖性。虽然SLC38A1对于T细胞随时间的持续存在和扩增以及肺部炎症是可有可无的，但它对Th1细胞驱动的实验性自身免疫性脑脊髓炎（EAE）至关重要，而对Th17细胞驱动的EAE则不然，并且它促成了Th1细胞驱动的炎症性肠病。SLC38A1缺陷部分通过减少细胞内谷氨酰胺以及破坏己糖胺生物合成和氧化还原调节，降低了Th1细胞中的mTORC1信号传导和糖酵解活性。同样，对SLC38转运体的药理学抑制延迟了EAE，但不影响肺部炎症。CD4 T细胞对氨基酸转运体的亚群和组织特异性依赖性可能指导选择性免疫疗法。
