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

Background Gamma-delta (gamma delta) 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 gamma delta T cells interact with the gut microbiota to maintain tolerance. Results We found that antibiotic treatment impaired oral tolerance and depleted intestinal gamma delta T cells, suggesting that the gut microbiota is necessary to maintain gamma delta T cells. We also found that mice deficient for gamma delta T cells (gamma delta(-/-)) had an altered microbiota composition that led to small intestine (SI) immune dysregulation and impaired tolerance. Accordingly, colonizing WT mice with gamma delta(-/-) microbiota resulted in SI immune dysregulation and loss of tolerance whereas colonizing gamma delta(-/-) mice with WT microbiota normalized mucosal immune responses and restored mucosal tolerance. Moreover, we found that SI gamma delta 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 gamma delta(-/-) mice rescued mucosal tolerance by promoting the growth of the gamma delta(-/-)-microbiota-depleted microbe Ruminococcus gnavus. Conclusions Taken together, we demonstrate that gamma delta T cell-selected microbiota is necessary and sufficient to promote mucosal tolerance, is mediated in part by gamma delta T cell secretion of fecal micro-RNAs, and is mechanistically linked to restoration of mucosal immune responses.

Automated summary

This study reveals that the interaction between intestinal gamma delta T cells and gut microbiota is crucial for maintaining mucosal tolerance. Antibiotic treatment disrupts oral tolerance and reduces the number of intestinal gamma delta T cells. Mice deficient in gamma delta T cells exhibit altered microbiota composition, which leads to immune dysregulation and impaired tolerance in the small intestine. Colonizing the deficient mice with normal microbiota restores mucosal immune responses and tolerance.