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.
- Lopez Krol, A.
- Nehring, H. P.
- Krause, F. F.
- Wempe, A.
- Raifer, H.
- Nist, A.
- Stiewe, T.
- Bertrams, W.
- Schmeck, B.
- Luu, M.
- Leister, H.
- Chung, H. R.
- Bauer, U. M.
- Adhikary, T.
- Visekruna, A.
Keywords
- Th17 cells
- Tregs
- histone lactylation
- immunometabolism
- lactate
