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Pyruvate metabolism controls epigenome remodeling during CD4+ T cell activation

Mocholi, E;Russo, L;Gopal, K;Ramstead, A;Hochrein, S;Vos, H;Geeven, G;Adegoke, A;Hoekstra, A;Es, R;Pittol, J;Vastert, S;Rutter, J;Radstake, T;Loosdregt, J;Berkers, C;Mokry, M;Anderson, C;O'Connell, R;Vaeth, M;Ussher, J;Burgering, B;Coffer, P;

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 generation of extra-mitochondrial pyruvate is an essential step for acetyl-CoA production and subsequent H3K27ac-mediated epigenome remodeling. In contrast, neither acetate/ACSS2 nor citrate/ACLY metabolism are required for activation-induced transcriptional changes. Furthermore, T cell activation results in the nuclear translocation of PDC and its association with both the p300 acetyltransferase and histone H3K27ac. These data support tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a novel therapeutic approach to specifically regulate antigen-driven T cell activation.