Lactate induces metabolic and epigenetic reprogramming of pro‐inflammatory Th17 cells

Increased lactate levels in the tissue microenvironment are a well‐known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17‐specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL‐17A production and upregulated Foxp3 expression through ROS‐driven IL‐2 secretion. Moreover, we observed increased levels of genome‐wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate‐treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro‐inflammatory T cell phenotypes into regulatory T cells.

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