EMBO Rep. 2022 Oct 10.
e54685
Aleksandra Lopez Krol,
Hannah P Nehring,
Felix F Krause,
Anne Wempe,
Hartmann Raifer,
Andrea Nist,
Thorsten Stiewe,
Wilhelm Bertrams,
Bernd Schmeck,
Maik Luu,
Hanna Leister,
Ho-Ryun Chung,
Uta-Maria Bauer,
Till Adhikary,
Alexander Visekruna.
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.
Keywords: Th17 cells; Tregs; histone lactylation; immunometabolism; lactate