Portal de Periódicos da CAPES

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

2023; BioMed Central; Volume: 11; Issue: 1 Linguagem: Inglês

10.1186/s40168-023-01478-1

2049-2618

Rafael M. Rezende, Laura M. Cox, Thaís G. Moreira, Shirong Liu, Selma Boulenouar, Fyonn Dhang, Danielle S. LeServe, Brenda Naemi Nakagaki, Juliana Romano Lopes, Bruna K. Tatematsu, Luísa Lemos, Julia Mayrink, Eduardo L.C. Lobo, Lydia Guo, Marília Garcia de Oliveira, Chantal Kuhn, Howard L. Weiner,

IL-33, ST2, and ILC Pathways

Abstract 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.