Mitochondrial C1qbp promotes differentiation of effector CD8 ⁺ T cells via metabolic-epigenetic reprogramming

Abstract

Early-activated CD8⁺ T cells increase both aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). However, whether and how the augmentation of OXPHOS regulates differentiation of effector CD8⁺ T cell remains unclear. Here, we found that C1qbp was intrinsically required for such differentiation in antiviral and antitumor immune responses. Activated <i>C1qbp</i>-deficient CD8⁺ T cells failed to increase mitochondrial respiratory capacities, resulting in diminished acetyl–coenzyme A as well as elevated fumarate and 2-hydroxyglutarate. Consequently, hypoacetylation of H3K27 and hypermethylation of H3K27 and CpG sites were associated with transcriptional down-regulation of effector signature genes. The effector differentiation of <i>C1qbp</i>-sufficient or <i>C1qbp</i>-deficient CD8⁺ T cells was reversed by fumarate or a combination of histone deacetylase inhibitor and acetate. Therefore, these findings identify C1qbp as a pivotal positive regulator in the differentiation of effector CD8⁺ T cells and highlight a metabolic-epigenetic axis in this process.