Lactate rewires metabolism of Th17 cells and promotes the regulatory T cell-like phenotype

• Applicant: Professor Dr. Alexander Visekruna
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548910661

CD4+ T cells play a central role in orchestrating protective immune reactions against pathogens, but they also drive adverse immune response, resulting in inflammation and autoimmune disorders such as inflammatory bowel disease (IBD) and multiple sclerosis (MS). Recently, we have shown that specific microbial metabolites derived from commensal bacteria such as the short-fatty acid pentanoate are capable of enhancing the anti-inflammatory immunity in experimental autoimmune encephalomyelitis (EAE) and T cell-mediated colitis by modulating the function of Th17 cells. Th17 cells were identified in 2006 as a novel T cell lineage, regulated by the lineage-specific transcription factor RORgt. Th17 cells have been found to crucially contribute to the immunepathogenesis of IBD and MS. In this project, we plan to explore metabolic, epigenetic and transcriptional mechanisms associated with effects of L-lactate, which is the end-product of glycolysis, and microbial molecule D-lactate on T cell differentiation. Thereby, in our preliminary data, we observe that both enantiomers of lactic acids, L- and D-lactate, are able to reprogram the pathogenic Th17 cells into Foxp3+ regulatory T cells by down-regulating the secretion of IL-17A and surface expression of IL-23 receptor, and by simultaneously inducing IL-2 production and Foxp3 expression. These seminal findings point out that small molecules D- and L-lactate are capable of reshaping T cell differentiation by inducing the expression of Foxp3 in Th17 cells. These preliminary observations provide a rationale to investigate these two molecules as protective factors in the context of intestinal inflammation and autoimmunity in the central nervous system (CNS). This hypothesis will be tested by combining genomic, metabolic, microbiological and immunologic approaches, supported by RNA sequencing and bioinformatics analysis.

• DFG Programme: Research Grants