Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells

Gut interleukin-17A (IL-17)-producing γδ T cells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ T cells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ T cells. Propionate acts directly on γδ T cells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ T cell functions and offer therapeutic perspectives of these cells. [Display omitted] •The gut microbiota represses IL-17 production by cecal γδ T cells•Short-chain fatty acids repress IL-17- and IL-22-producing γδ T cells•Propionate acts on γδ T cell functionalities by inhibiting histone deacetylase•Propionate represses IL-17 production by human γδ T cells from patients with IBD Dupraz et al. demonstrate that short-chain fatty acids, particularly propionate, reduce IL-17 production by mouse intestinal γδ T cells and human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD). These microbiota-derived metabolites act directly on γδ T cells in a histone deacetylase-dependent manner.