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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Balmer, Maria L 
Ma, Eric H 
Thompson, Andrew J 
Epple, Raja 
Unterstab, Gunhild 

Abstract

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.

Description

Keywords

acetate, glutaminolysis, immunometabolism, immunopathology, infection, memory CD8+ T cells, Acetates, Animals, Anti-Inflammatory Agents, CD8-Positive T-Lymphocytes, Female, Humans, Male, Mice, Mice, Inbred C57BL

Journal Title

Cell Metab

Conference Name

Journal ISSN

1550-4131
1932-7420

Volume Title

32

Publisher

Elsevier BV