Effective reprogramming of exhausted CD8 T cells by a novel microbial-derived metabolite 2846

Description Exhaustion of CD8 T cells during cancer or chronic infections remains a significant barrier to T cell immunotherapies. Recent studies showed that distinct epigenetic changes drive exhaustion by silencing effector and memory-related genes, thereby imprinting the dysfunctional state of exhausted T cells (TEX). Thus, targeting epigenetic regulation of exhaustion is essential to rejuvenating TEX cells. Short chain fatty acids (SCFAs) are emerging as an important link between cellular metabolism and gene regulation. In particular, some SCFAs that are naturally produced by human microbiota were shown to influence host immune responses through epigenetic mechanisms. To elucidate their impact on the epigenetic programming of TEX cells, we employed novel in vitro models of T cell exhaustion that induce stable terminal dysfunction in human and mouse CD8 T cells. We found that treatment with a specific microbial SCFA induced a striking recovery of polyfunctionality and memory programs within both human and mouse dysfunctional T cells. Importantly, the enhanced effector functions were sustained following the withdrawal of SCFA treatment, indicating stable reprogramming of TEX cells. These findings identify a novel microbial SCFA as a metabolic-epigenetic switch that reactivates effector programs in TEX cells, while blocking terminal exhaustion. This offers insights for new therapeutic strategies to epigenetically reprogram TEX cells and enhance the efficacy of T cell immunotherapies.