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

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. [Display omitted] •Acetate concentrations are increased at sites of inflammation•TCR signaling and acetate reduce ACSS1/2 expression in memory CD8+ T cells•Glutaminolysis is boosted and calcium flux inhibited by acetate•Local acetate accumulation protects from immunopathology Balmer et al. uncover that acetate abundance steadily increases at sites of inflammation. Acetate directly affects the activation and function of memory CD8+ T cells by activating glutaminolysis and reducing calcium availability. In vivo, the integrated pro- and anti-inflammatory activities of acetate balance immune control with immunopathology.