Mitochondrial ATP production links chromatin accessibility to T cell differentiation and function 2258461

Abstract Introduction Immune elimination of chronic infection or cancer requires cytotoxic CD8 T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short chain fatty acid, D-α-hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8 T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function. Methods Murine T cells were tested in response to D-α-hydroxybutyrate by flow cytometry, RNAseq, ATACseq and metabolomics. Results DAHB promotes OXPHOS by inducing fatty acid oxidation which leads to an elevated creatine-phosphate buffer. Creatine-phosphate regenerates ATP to support chromatin remodeling and expression of effector genes. DAHB enhances immune checkpoint blockade and T cell adoptive transfer in tumor settings. Conclusion Mitochondrial ATP and phosphocreatine supports chromatin remodeling for cytotoxic T cell gene expression. Funding Source n/a Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)