Memory CD8+ T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function

• Published in: Immunity (Cambridge, Mass.) Vol. 44; no. 6; pp. 1312 - 1324
• Main Authors: Balmer, Maria L., Ma, Eric H., Bantug, Glenn R., Grählert, Jasmin, Pfister, Simona, Glatter, Timo, Jauch, Annaïse, Dimeloe, Sarah, Slack, Emma, Dehio, Philippe, Krzyzaniak, Magdalena A., King, Carolyn G., Burgener, Anne-Valérie, Fischer, Marco, Develioglu, Leyla, Belle, Réka, Recher, Mike, Bonilla, Weldy V., Macpherson, Andrew J., Hapfelmeier, Siegfried, Jones, Russell G., Hess, Christoph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2016; Elsevier Limited
• Subjects: Acetates - metabolism; Acetyl-CoA C-Acetyltransferase - metabolism; Animals; ATP Citrate (pro-S)-Lyase - metabolism; Bacteria; Bacterial infections; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cells, Cultured; E coli; Enzymes; Experiments; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Glycolysis; Hypotheses; Immunity, Innate; Immunologic Memory; Infections; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - immunology; Liver; Lymphocytes; Medical research; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Processing, Post-Translational; Salmonella; Stress, Physiological - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.03.016

How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8+ T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8+ T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8+ T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8+ T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8+ T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness. [Display omitted] •Serum acetate levels rapidly increase following systemic bacterial infection•Memory CD8+ T cells take up acetate and expand their acetyl-CoA pool•Increased acetyl-CoA levels catalyze functional activity of GAPDH by acetylation•Augmented glycolytic flux rates boost rapid recall responses of memory CD8+ T cells How systemic metabolic alterations during acute infections impact immune-cell function remains poorly understood. Hess and colleagues demonstrate that acetate rapidly increases during infections, which drives acetylation of GAPDH in memory CD8+ T cells and thereby catalyzes the rapid recall response.