Pyruvate metabolism controls chromatin remodeling during CD4+ T cell activation
Enric Mocholí, Laura Russo, Keshav Gopal, Andrew G. Ramstead, Sophia M. Hochrein, Harmjan R. Vos, Geert Geeven, Adeolu Adegoke, Anna T. Hoekstra, Robert M. van Es, José M. Ramos Pittol, Sebastiaan J. Vastert, Jared Rutter, Timothy R. D. J. Radstake, Jorg van Loosdregt, Celia R. Berkers, Michal Mokrý, Colin C. Anderson, Ryan M. O’Connell, Martin Vaeth, John R. Ussher, Boudewijn Burgering, Paul J. Coffer
Abstract
Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.