Title: Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection
Author: Maria L. Balmer, Eric H. Ma, Andrew Thompson, Raja Epple, Gunhild Unterstab, Jonas Ltscher, Philippe Dehio, Christian M. Schürch, Jan D. Warncke, Galle Perrin, Anne-Kathrin Woischnig, Jasmin Grhlert, Jordan Lliger, Nadine Assmann, Glenn R. Bantug, Olivier P. Schren, Nina Khanna, Adrian Egli, Lukas Bubendorf, Katharina Rentsch, Siegfried Hapfelmeier, Russell G. Jones, Christoph Hess
Abstract: Serum acetate increases upon systemic infection. Acutely, assimilation of acetateexpands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Herewe show that at sites of infection, high acetate concentrations are being reached,yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, beingthus largely excluded from incorporation into cellular metabolic pathways, now haddifferent effects, namely (1) directly activating glutaminase, thereby augmentingglutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggeredcalcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducingimmunopathology. This indicates that, during different stages of the immune response,the same metabolite—acetate—induces distinct immunometabolic programs within the samecell type.