Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.

Balmer, Maria L; Ma, Eric H; Thompson, Andrew J; Epple, Raja; Unterstab, Gunhild; Lötscher, Jonas; Dehio, Philippe; Schürch, Christian M; Warncke, Jan D; Perrin, Gaëlle; Woischnig, Anne-Kathrin; Grählert, Jasmin; Löliger, Jordan; Assmann, Nadine; Bantug, Glenn R; Schären, Olivier P; Khanna, Nina; Egli, Adrian; Bubendorf, Lukas; Rentsch, Katharina; ... (2020). Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection. Cell metabolism, 32(3), 457-467.e5. Elsevier 10.1016/j.cmet.2020.07.004

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Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands 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. Here we 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, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type.

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