Mus musculus Genome sequencing

Memory CD8+ T cells play a crucial role in protective immunity to infection and cancer with the capability to mount robust recall responses. Although the developmental and transcriptional programs important for the generation of memory cells have been largely identified, the regulatory mechanisms that control such key transcriptional factors to affect the formation of memory CD8+ T cell remain less known. Here we discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi-functional protein, was highly expressed in memory CD8+ T cells and played a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to viral infection and tumor. Specific ablation of ECSIT in T cells markedly impaired the generation of memory CD8+ T cells in a cell-intrinsic manner accompanied with the decreased transcriptional level and regulation of TCF-1 that is a key player in the development, maintenance, and function of CD8+ memory T cell. Loss of ECSIT led to metabolic changes with significant reduction in fumarate, which promotes H3K4me3 demethylation of TCF-1 promoter region by histone demethylase KDM5 and its decreased expression that thus disrupt the differentiation and function of CD8+ memory T cell culminating in the impairment of antiviral and antitumor. We also showed that the expression of ECSIT was positively correlated with CD8+ memory T cell progenitors and the survival of patients with cancer and highlighted the potential strategy of combining DMF and PD-L1 inhibition for immunotherapy.