CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation

CCR6 is a G-protein-coupled receptor that binds to its ligand CCL20. Th17 and Foxp3⁺CD4⁺ T cells express CCR6, enabling their migration to inflamed tissues with unique metabolic environments. The factors that regulate their metabolic adaptation and functional roles in these tissues remain unclear. Using inflammatory bowel disease patient samples and experimental colitis models in mice, we demonstrated that the intrinsic signaling of CCL20-CCR6 in CD4⁺ T cells promotes the differentiation of inflammatory Th1-like Th17 cells (T-bet⁺RORγt⁺) during colitis. This signaling induces the rapamycin-sensitive phosphorylation of PI3K, Akt, mTORC1, and STAT3 in a CCR6-dependent manner. RNA-seq and proteomics analysis revealed that the addition of CCL20 during Th17 differentiation affects several metabolic pathways, including energy metabolism. CCL20 significantly increased glycolysis and inhibited oxidative phosphorylation, thereby driving the differentiation of pathogenic Th17 cells. Our findings suggest that alterations in CCR6-induced changes in Th17 metabolism offer an interesting therapeutic target for gut inflammation and autoimmunity.