CRIF1 deficiency induces FOXP3 ^LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity

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.