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 impaired oral tolerance and depleted intestinal γδ T cells, suggesting that the gut microbiota is necessary to maintain γδ T cells. We also found that mice deficient for γδ T cells (γδ(−/−)) had an altered microbiota composition that led to small intestine (SI) immune dysregulation and impaired tolerance. Accordingly, colonizing WT mice with γδ(−/−) microbiota resulted in SI immune dysregulation and loss of tolerance whereas colonizing γδ(−/−) mice with WT microbiota normalized mucosal immune responses 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 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, is mediated in part by γδ T cell secretion of fecal micro-RNAs, and is mechanistically linked to restoration of mucosal immune responses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-023-01478-1.