biostudies-literatureKaymak INIAID NIH HHSFonds de Recherche du Québec—SantéNational Institutes of HealthDaymon Runyon FoundationChan Zuckerberg InitiativeCancer Research InstituteNational Institute of Allergy and Infectious DiseasesFonds de Recherche du Québec-SantéCancer Research SocietyPaul G. Allen Frontiers GroupSalk Pioneer FundNational Cancer InstituteNCI NIH HHSNIH HHSe20231820https://www.ebi.ac.uk/biostudies/studies/S-EPMC11329787biostudies-literatureUnknown221(9)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 ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). 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 metabThe Journal of experimental medicineACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.PMC11329787R01AI165722R21 AI151986R01 AI066232R21AI153997T32 CA251066T32CA251066-01A1R01 AI165722PJT 192049R21 AI1539972495-23Kaymak IMa SWatson MJDahabieh MSWilliams KSFu ZVander Ark AKitchen-Goosen SMSheldon RDShen HMabvakure BMOswald BMKaech SMVos MJohnson BKKingsbury GASousa CMDeCamp LMKrawczyk CMMa EHRoy DGRoddy TPLuda KMMuhire BSamborska BLau KJones RGFan ZPfalseACLY and ACSS2 link nutrient-dependent chromatin accessibility to 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 ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). 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 metab2024-01-01T00:00:00Z2024 Sep2026-06-02T20:16:35.593Z2025-04-07T07:53:20.514ZS-EPMC113297873915048210.1084/jem.20231820