Recently identified human FOXP3 low CD45RA − inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (T regs ). In spite of their implication in tumors, the mechanism for generation of FOXP3 low CD45RA − INS cells in vivo is unclear. We showed that the FOXP3 low CD45RA − cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in T regs bore Foxp3 low INS-T regs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate–mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate–derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency–induced Foxp3 low INS-T regs suppressed tumor growth in an IFN-γ–dependent manner. Thus, CRIF1 deficiency–mediated mitochondrial dysfunction results in the induction of Foxp3 low INS-T regs including FOXP3 low CD45RA − cells that promote antitumor immunity.

中文翻译：

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CRIF1缺陷诱导FOXP3 LOW炎症非抑制性调节T细胞，从而促进抗肿瘤免疫

最近发现的人类 FOXP3低的CD45RA-与传统的调节性 T 细胞 (T规则）。尽管 FOXP3 的产生机制与肿瘤有关，但低的CD45RA-INS细胞在体内的作用尚不清楚。我们证明了 FOXP3低的CD45RA-人类肿瘤细胞中 CRIF1（一种重要的线粒体调节因子）的表达减弱。 T 区 CRIF1 缺陷的小鼠规则钻孔 Foxp3低的INS-T规则线粒体功能障碍和代谢重编程。增强的谷氨酰胺分解激活了α-酮戊二酸-mTORC1轴，通过诱导EOMES和SATB1表达来促进促炎细胞因子的表达。此外，染色质调控区域的开放性伊冯和伊尔4基因增加，促进 EOMES/SATB1 结合。增加的α-酮戊二酸衍生的2-羟基戊二酸通过甲基化下调Foxp3表达福克斯p3基因调控区。此外，CRIF1 缺陷诱导的 Foxp3低的INS-T规则以 IFN-γ 依赖性方式抑制肿瘤生长。因此，CRIF1 缺陷介导的线粒体功能障碍导致 Foxp3 的诱导低的INS-T规则包括FOXP3低的CD45RA-促进抗肿瘤免疫的细胞。