Friday, May 9, 2025
5/9/2025
Human M Cells Require Coronin 1a - Project Summary/Abstract The regulation of luminal surveillance and antigen sampling across mucosal surfaces remains an important and fundamental area of investigation. This is particularly true for the intestinal epithelium, which is constantly challenged to maintain homoeostasis with the complex microbiome while protecting the mucosa from pathogenic organisms. Microfold (M) cells of the Peyer’s patch (PP) play a crucial role in immune surveillance of the gut environment by transporting luminal antigens to underlying immune cells. Through their ability to move cargo across the epithelium, M cells can (1) benefit the host by translocating luminal contents (e.g. dietary antigens, microbes, vaccines) to induce appropriate innate and adaptive immune responses or (2) harm the host upon infection by invasive pathogens. However, the mechanisms responsible for antigen uptake by M cells and delivery to immune cells are not completely understood in humans. The significance of our proposed research is that we will define the basic mechanism responsible for the major function (i.e. transcytosis) of human M cells. Revealing what controls transcytosis in human M cells has the potential to improve our understanding of how luminal gut contents are delivered to immune cells under normal conditions or during enteric infections. Our recent discoveries using human enteroids enriched in M cells as a relevant ex vivo model of the human PP epithelium demonstrate that (1) coronin 1a is required for uptake and transcytosis of luminal cargo across human M cells, (2) update and transcytosis of gut antigens occurs by a apical-dependent bulk endocytosis process that involves coronin 1a-mediated signaling, and (3) PP macrophages synergize with M cell-expressing human enteroids to increase M cell-dependent uptake and transcytosis of luminal gut. SPECIFIC AIMS: We propose to test the hypotheses that human M cell expressing enteroids respond to luminal microbial and serosal immune signals to induce uptake and transcytosis of gut cargo by a unique coronin 1a dependent mechanism. Our central hypotheses are that coronin 1a expression in human M cells is necessary for: (i) terminal differentiation of FAE progenitor cells to become functionally mature M cells, (ii) synergism between PP macrophages and the human FAE to enhance luminal sampling of gut antigens, and (iii) mediating luminal- and serosal-derived signals that stimulate entry and transcytosis of luminal gut cargo to underlying immune cells. The studies will improve our understanding of how human M cells function and may lead to development of novel therapeutic strategies to treat GI disorders, such as Crohn’s disease, or even possibly development of new strategies to enhance oral vaccine delivery.
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