Gamma-delta T cells modulate the microbiota and fecal micro-RNAs to maintain mucosal tolerance

Background: Gamma-delta (γδ) T cells are a major cell population in the intestinal mucosa and are key mediators of mucosal tolerance and microbiota composition. Little is known about the mechanisms by which intestinal γδ T cells interact with the gut microbiota to maintain tolerance. Results: We found that antibiotic treatment depleted intestinal γδ T cells and impaired oral tolerance, suggesting that the gut microbiota is necessary to maintain γδ T cells. We also found that mice deficient for γδ T cells (γδ −/− ) developed a microbial dysbiosis that led to small intestine (SI) inflammation and impaired tolerance. Accordingly, colonizing WT mice with γδ −/− microbiota resulted in SI inflammation and loss of tolerance whereas colonizing γδ −/− mice with WT microbiota ameliorated inflammation and restored mucosal tolerance. Moreover, we found that SI γδ T cells shaped the gut microbiota and regulated intestinal homeostasis by secreting the fecal micro-RNA let-7f. Importantly, oral administration of let-7f to γδ −/− mice decreased inflammation and rescued mucosal tolerance by promoting the growth of the γδ −/− microbiota depleted microbe Ruminococcus gnavus . Conclusions: Taken together, we demonstrate that γδ T cell-selected microbiota is necessary and sufficient to promote mucosal tolerance, which is mechanistically linked to γδ T cell secretion of fecal micro-RNAs.