Role of myosin IIA in the small intestine immunosurveillance by dendritic cells

Abstract : Several routes for antigen capture have been described in the small intestine, mainly upon pathogenic infection: direct sampling by Dendritic Cells (DCs), sampling by macrophages that deliver antigens to DCs in the stroma, antigenic passage through goblet cells. Previous in vitro work in the lab showed that myosin IIA is essential to coordinate antigen uptake and processing with DC migration. The objective of my thesis was to combine several imaging methods including intravital microscopy, ex vivo confocal microscopy and immunofluorescence on gut tissue to flow cytometry in order to unravel the impact of myosin IIA on DC physiology in vivo. My work shows that CD103+CD11b+ DCs, which are unique to the gut, constantly patrol the epithelium of the small intestine at steady state: they are recruited from the lamina propria (LP) and penetrate into the epithelium by transmigrating through the basal membrane that separates these two compartments. DC transmigration requires myosin IIA in vivo. Remarkably, we found that DC transmigration into the epithelium occurs mainly in the upper parts of the small intestine, the duodenum and the jejunum, but is not observed in the ileum. DC transmigration does not require the gut microbiota but relies on retinal, a vitamin A metabolite of that they convert into its active form all-trans retinoic acid (AtRA). Strikingly, single cell RNA-seq showed that intra-epithelial CD103+CD11b+ DCs constitute a homogenous cell population with a distinct transcriptomic signature from their LP counterpart. They are enriched with RNA related to antigen presentation, autophagy and lysosome pathways. Our results further suggest that these cells have a different function from LP CD103+CD11b+ DCs, as they do not significantly impact proliferation or differentiation of T helper lymphocytes but control the CD8+αβ intraepithelial lymphocytes (IELs) pool. These findings highlight the importance of the epithelial tissue as a first line of defense against pathogens in the upper parts of the small intestine. They also raise new questions about the regulation of the immune response in the epithelium and the mutual influences between lumen, epithelium and intestinal lamina propria.
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Violaine Randrian. Role of myosin IIA in the small intestine immunosurveillance by dendritic cells. Immunology. Université Sorbonne Paris Cité, 2017. English. ⟨NNT : 2017USPCB038⟩. ⟨tel-02120786⟩

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