Recently identified human FOXP3^lowCD45RA⁻ 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^lowCD45RA⁻ INS cells in vivo is unclear. We showed that the FOXP3^lowCD45RA⁻ cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in T_regs bore Foxp3^lowINS-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^lowINS-T_regs suppressed tumor growth in an IFN-γ–dependent manner. Thus, CRIF1 deficiency–mediated mitochondrial dysfunction results in the induction of Foxp3^lowINS-T_regs including FOXP3^lowCD45RA⁻ cells that promote antitumor immunity.

中文翻译：

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CRIF1缺陷诱导FOXP3LOW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CD45RA ^-炎症非抑制 (INS) 细胞产生促炎细胞因子，表现出抑制性降低，并与传统的调节性 T 细胞 (T _regs ) 不同，促进抗肿瘤免疫。尽管它们对肿瘤有影响，但体内产生 FOXP3^低CD45RA ^- INS 细胞的机制尚不清楚。我们发现，人类肿瘤中的FOXP3^低CD45RA ^-细胞表现出 CRIF1（一种重要的线粒体调节因子）的表达减弱。 T _reg中 CRIF1 缺陷的小鼠具有 Foxp3^低INS-T _reg，并伴有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， Ifng和Il4基因调控区的染色质开放性增加，有利于 EOMES/SATB1 结合。 α-酮戊二酸衍生的 2-羟基戊二酸增加，通过甲基化Foxp3基因调控区域来下调 Foxp3 的表达。此外，CRIF1 缺陷诱导的 Foxp3^低INS-T_调节因子以 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会导致 Foxp3^低INS-T_调节细胞的诱导，包括 FOXP3^低CD45RA ^-细胞，从而促进抗肿瘤免疫。