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

Abstract

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 <i>Ifng</i> and <i>Il4</i> genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the <i>Foxp3</i> 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.