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Les cellules MAIT et la riboflavine dans les interactions hôte-microbiote

Abstract : Mucosal associated invariant T (MAIT) cells are an evolutionary conserved T cell subset, which recognize riboflavin precursor derivatives presented by MR1. Intestinal bacteria from the Bacteroidetes and Proteobacteria phyla can produce MAIT antigens, suggesting a direct interplay between MAIT cells and the microbiota. In humans, MAIT cells have been implicated in pathologies associated with intestinal dysbiosis such as inflammatory bowel diseases, but the role of MAIT cells in these diseases remains unknown. Increased levels of oxygen and oxidative stress are hallmarks of intestinal inflammation, and riboflavin contributes to bacterial respiration and to oxidative stress resistance, suggesting increased needs for riboflavin during intestinal inflammation. Supporting this hypothesis, bacteria possessing the riboflavin biosynthesis pathway are enriched in Crohn’s disease patients.In the first part of this work, we explored the hypothesis that MAIT cells monitor a bacterial metabolic pathway associated with altered gut ecosystem. We showed that hypoxia disruption in the colon, upon antibiotic treatment or dextran sodium sulfate (DSS)-induced colitis, increased MAIT antigen production by the microbiota. We sequenced the 16S rRNA genes from the cecum of antibiotic- and DSS-treated mice, and analyzed expression of the riboflavin pathway genes in the Helicobacter hepaticus model of colitis. Dysanaerobiosis was associated with expansion of Enterobacteriaceae upon vancomycin treatment, and Bacteroidaceae and Enterobacteriaceae in colitic mice. Riboflavin production provided a fitness advantage to Escherichia coli in the inflamed intestine. Both Bacteroidaceae and Enterobacteriaceae can produce high amounts of MAIT antigens in vitro. In the H. hepaticus model of colitis, ribD, which controls MAIT antigen production, was over-expressed by Bacteroidaceae, Clostridiaceae and Enterobacteriaceae during colitis. MAIT antigens crossed the intestinal barrier and induced T cell receptor (TCR) signalling in MAIT cells, which produced the tissue-repair mediator amphiregulin and reduced colitis severity. In the second part of this work, we characterized MAIT cells in the ileal environment, wherein high levels of oxygen have been observed at steady state. A range of bacteria that encode the riboflavin pathway populated the ileum, however ileal MAIT cells were not activated through TCR engagement and expressed distinct phenotypic profiles. We discuss the future studies that will be needed to understand MAIT-microbiota interactions in the ileum.Collectively, in the colon, MAIT cells directly sense and react to changes in bacterial metabolism associated with intestinal inflammation and provide host protection in return. This new host-microbiota interaction may explain MAIT cell activation in other pathologies associated with dysbiosis such as colorectal cancer.
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Submitted on : Thursday, June 2, 2022 - 1:05:37 AM
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Yara El Morr. Les cellules MAIT et la riboflavine dans les interactions hôte-microbiote. Immunology. Université Paris sciences et lettres, 2021. English. ⟨NNT : 2021UPSLS050⟩. ⟨tel-03685193⟩



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