ACLY 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 metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.
Authors
- Benjamin K. Johnson (ORCID: https://orcid.org/0000-0002-1482-1032)
- Katarzyna M. Luda (ORCID: https://orcid.org/0000-0002-6647-3981)
- Zi Peng Fan (ORCID: https://orcid.org/0009-0004-0094-6514)
- Irem Kaymak (ORCID: https://orcid.org/0000-0003-0772-512X)
- Brandon M. Oswald (ORCID: https://orcid.org/0000-0002-4147-2915)
- Lisa M. DeCamp (ORCID: https://orcid.org/0000-0002-4682-7586)
- Hui Shen (ORCID: https://orcid.org/0000-0001-9767-4084)
- Connie M. Krawczyk (ORCID: https://orcid.org/0000-0002-2468-5986)
- Batsirai Mabvakure (ORCID: https://orcid.org/0000-0002-2760-5443)
- Matthew Vos (ORCID: https://orcid.org/0009-0008-9669-4380)
- H. Eric (ORCID: https://orcid.org/0000-0001-8556-980X)
- Brejnev Muhire (ORCID: https://orcid.org/0000-0002-5594-1348)
- Ryan D. Sheldon (ORCID: https://orcid.org/0000-0002-1573-9719)
- Russell G. Jones (ORCID: https://orcid.org/0000-0003-2250-4675)
- McLane J. Watson
- Cristovão M. Sousa (ORCID: https://orcid.org/0009-0005-2195-3307)
- Bożena Samborska (ORCID: https://orcid.org/0000-0002-1871-4699)
- Dominic G. Roy (ORCID: https://orcid.org/0000-0002-6044-0118)
- Susan M. Kitchen-Goosen (ORCID: https://orcid.org/0000-0001-9291-056X)
- Michael S. Dahabieh
- Thomas P. Roddy
- Kelsey S. Williams
- Susan M. Kaech (ORCID: https://orcid.org/0000-0003-1674-1420)
- Zhen Fu (ORCID: https://orcid.org/0000-0002-8120-590X)
- Alexandra Vander Ark (ORCID: https://orcid.org/0000-0002-1194-810X)
- Shixin Ma
- Kin H. Lau (ORCID: https://orcid.org/0000-0002-7405-1551)
- Gillian A. Kingsbury
Institutions
- University of Copenhagen (DK)
- Salk Institute for Biological Studies (US)
- Van Andel Institute (US)
- Montreal Heart Institute (CA)
- Novo Nordisk Foundation (DK)
- Agios Pharmaceuticals (United States) (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1084/jem.20231820
- Citations
- 27
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 7.93
Funders
- Cancer Research Institute
- Pioneer Fund
- Cancer Research Society
- Chan Zuckerberg Initiative
- Agios Pharmaceuticals
- Paul G. Allen Frontiers Group
- Servier
- National Institutes of Health
- Fonds de Recherche du Québec - Santé
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases