Nutrients are emerging regulators of adaptive immunity¹. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism^2,3,4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein–protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (T_reg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and T_reg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse T_reg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

营养素是适应性免疫的新兴调节剂¹。选择性营养素与免疫信号相互作用以激活雷帕霉素复合物 1 (mTORC1) 的机制靶点，这是细胞代谢的关键驱动因素^2,3,4，但这些环境信号如何整合用于免疫调节仍不清楚。在这里，我们使用全基因组 CRISPR 筛选与蛋白质-蛋白质相互作用网络相结合，以确定在小鼠调节性 T (T reg ) 细胞中介导免疫受体和营养依赖性信号转导至 mTORC1 的调节_模块。SEC31A 被确定为通过与 GATOR2 组件 SEC13 相互作用来促进 mTORC1 激活，以保护其免受 SKP1 依赖性蛋白酶体降解。因此，SEC31A 的丢失会损害 T 细胞启动和 T _reg小鼠的抑制作用。此外，SWI/SNF 复合物限制氨基酸传感器 CASTOR1 的表达，从而增强 mTORC1 的激活。此外，我们发现 CCDC101 相关的 SAGA 复合物是 mTORC1 的有效抑制剂，它限制葡萄糖和氨基酸转运蛋白的表达并维持体内 T 细胞静止。小鼠 T _reg细胞中特定缺失Ccdc101会导致不受控制的炎症，但会提高抗肿瘤免疫力。总的来说，我们的结果建立了表观遗传和翻译后机制，支持营养转运蛋白、传感器和换能器如何与免疫信号相互作用以实现 mTORC1 活性的三层调节，并确定它们在许可 T 细胞免疫和免疫耐受中的关键作用。