ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme Acly (ATP citrate lyase). However, ablation of Acly triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by Acss2 (acyl-CoA synthetase short chain family member 2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When Acly is functional, Acss2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, deletion of Acly renders CD8 T cells dependent on acetate (via Acss2) to maintain acetyl-CoA production and effector function. Thus, together Acly and Acss2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function. Overall design: C57BL/6 mice (3 biological replicates) were infected with LCMV-Armstrong. At 8 dpi, mice were sacrificed, and single cell suspensions generated