Mitochondrial C1qbp Promotes Differentiation Of Effector CD8~+ T Cells Via Metabolic-epigenetic Reprogramming

Infection with viruses or bacteria,antigen-specific CD8+T cells will clonally expand and differentiate into effector cells.Early-activated CD8+T cells increase both aerobic glycolysis and mitochondrial oxidative phosphorylation to meet the energy and nutrient demands.C1qbp is required for mitochondrial OXPHOS since it can promote mitochondrial translation as an RNA-binding protein.However,the role of Clqbp in T cells is not clear.Whether OXPHOS,especially its transient increase,contributes to epigenetic regulation of differentiation and function of effector CD8+T cells,has not been uncovered.We generated C1qbpfl/fl dLck-Cre mice with T cell-specific C1qbp deficiency.Here we reported that C1qbp-deficient mice exhibited substantial cell-intrinsic defect in differentiation of effector CD8+T cells and cytokine production after acute LCMV infection or subcutaneously melanoma transplantation.Activated C1qbp-deficient CD8+T cells were not able to increase OXPHOS,resulting in diminished acetyl-CoA as well as elevated 2-hydroxyglutarate(2-HG)and fumarate.Hypoacetylation of H3K27 and hypermethylation of H3K27 and CpG sites,were associated with transcriptional downregulation of effector signature genes in C1qbp-deficient CD8+T cells.Furthermore,pretreatment of WT or C1qbp-deficient CD8+T cells with fumarate or combination of histone deacetylase inhibitor tubastatin A and acetate(TA/Ac)respectively,reversed their capacities to differentiate into effector CD8+T cells.Taken together,our data suggested that Clqbp is essential for the differentiation of effector CD8+T cells through a metabolic-epigenetic axis.Our study made progress in the molecular mechanism of differentiation of effector CD8+T cells,and provided a theoretical foundation for discovering new targets of tumor immunotherapy.