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. Display omitted •PDH is required for histone acetylation and transcription after T cell activation•MPC1 and ACLY are not required for T cell activation and transcriptional reprogramming•T cell activation leads to PDH nuclear translocation close to chromatin-remodeling complexes After T cell activation, histone acetylation and transcriptional reprogramming require glycolysis and the pyruvate dehydrogenase (PDH)-dependent production of extramitochondrial acetyl-CoA. Mocholi et al. show that PDH translocates to the nucleus close to chromatin-remodeling complexes, highlighting how metabolic and histone-modifying enzymes cooperate in regulating T cell activation.