Human Intestinal Enteroids Model MHC-II in the Gut Epithelium

Wosen, Jonathan; Ilstad-Minnihan, Alexandra; Co, Julia Y.; Jiang, Wei; Mukhopadhyay, Dhriti; Fernandez‐Becker, Nielsen; Kuo, Calvin J.; Amieva, Manuel R.; Mellins, Elizabeth

doi:10.3389/fimmu.2019.01970

Cited by 28 publications

(27 citation statements)

References 35 publications

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“…M cells were speculated to present antigen directly to antigen-presenting cells. To mimic pathologic and infection conditions in the small intestine, 31 we treated M-cellenriched ileal enteroids with human IFN-g. Like non-M-cellcontaining human enteroids, 32 we observed strong major histocompatibility complex (MHC) class II (MHC-II) staining, and, importantly, detected co-localization of GP2 and MHC-II (Supplementary Figure 5D). These results are consistent with the idea that human M cells can contribute to MHC-IIrestricted antigen presentation in the small intestine and with previous finding of MHC-II staining in M cells in human PPs.…”

Section: Resultsmentioning

confidence: 82%

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

et al. 2020

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Human and mouse ileum tissues Intestinal enteroid culture Functional M cells Enteric viruses RANKL RA, LT WRN See editorial on page 34. BACKGROUND & AIMS: Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer's patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids. METHODS: We analyzed transcriptome data from mouse Peyer's patches to identify cell populations in close proximity to M cells. We used the human enteroid system to determine which cytokines were required to induce M-cell differentiation. We performed transcriptome, immunofluorescence, scanning electron microscope, and transcytosis experiments to validate the development of phenotypic and functional human M cells. RESULTS: A combination of retinoic acid and lymphotoxin induced differentiation of glycoprotein 2-positive human M cells, which lack apical microvilli structure. Upregulated expression of innate immune-related genes within M cells correlated with a lack of viral antigens after rotavirus infection. Human M cells, developed in the enteroid system, internalized and transported enteric viruses, such as rotavirus and reovirus, across the intestinal epithelium barrier in the enteroids. CONCLUSIONS: We identified signaling pathways required for differentiation of intestinal M cells, and used this information to create a robust culture method to develop human M cells with capacity for internalization and transport of viruses. Studies of this model might increase our understanding of antigen presentation and the systemic entry of enteric pathogens in the human intestine.

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Section: Resultsmentioning

confidence: 82%

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

et al. 2020

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“…The latter can be divided into distinct compartments according to ultrastructural morphology, which includes multi‐vesicular bodies (MVB) 42 . Several studies characterized the localization of MHC class II molecules within IECs in endoscopic biopsies of healthy controls and IBD patients 33,43 as well as human small intestinal organoids 44 . In the healthy human gut, the late endosomal structure MVB harboured the majority of MHC class II molecules, but they were also observed at the basolateral cell membrane with faint expression at the apical membrane 33,43 .…”

Section: Mhc Class II Expression and Localization In Iecsmentioning

confidence: 99%

Why do intestinal epithelial cells express MHC class II?

2020

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Summary Intestinal epithelial cells (IECs) constitute the border between the vast antigen load present in the intestinal lumen and the mucosal immune compartment. Their ability to express antigen processing and presentation machinery evokes the question whether IECs function as non‐conventional antigen‐presenting cells. Major histocompatibility complex (MHC) class II expression by non‐haematopoietic cells, such as IECs, is tightly regulated by the class II transactivator (CIITA) and is classically induced by IFN‐γ. As MHC class II expression by IECs is upregulated under inflammatory conditions, it has been proposed to activate effector CD4+ T (Teff) cells. However, other studies have reported contradictory results and instead suggested a suppressive role of antigen presentation by IECs, through regulatory T (Treg)‐cell activation. Recent studies investigating the role of MHC class II + exosomes released by IECs also reported conflicting findings of either immune enhancing or immunosuppressive activities. Moreover, in addition to modulating inflammatory responses, recent findings suggest that MHC class II expression by intestinal stem cells may elicit crosstalk that promotes epithelial renewal. A more complete understanding of the different consequences of IEC MHC class II antigen presentation will guide future efforts to modulate this pathway to selectively invoke protective immunity while maintaining tolerance to beneficial antigens.

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“…Research groups have now shown that innate immune responses of IEC are modulated by the removal of Wnt3a conditioned medium, which alters the state of differentiation of IEC. For instance, removal of Wnt3a was shown to induce MHC II expression which can in turn promote TLR-triggered innate immune responses 48 . Similarly, the presence of anti-oxidants in the HISC medium have also been shown to influence innate immune responses of IEC 49 .…”

Section: Discussionmentioning

confidence: 99%

Development of a human primary gut-on-a-chip to model inflammatory processes

Beaurivage

Kanapeckaitė

Loomans

et al. 2020

Sci Rep

106

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Inflammatory bowel disease (IBD) is a complex multi-factorial disease for which physiologically relevant in vitro models are lacking. Existing models are often a compromise between biological relevance and scalability. Here, we integrated intestinal epithelial cells (IEC) derived from human intestinal organoids with monocyte-derived macrophages, in a gut-on-a-chip platform to model the human intestine and key aspects of IBD. The microfluidic culture of IEC lead to an increased polarization and differentiation state that closely resembled the expression profile of human colon in vivo. Activation of the model resulted in the polarized secretion of CXCL10, IL-8 and CCL-20 by IEC and could efficiently be prevented by TPCA-1 exposure. Importantly, upregulated gene expression by the inflammatory trigger correlated with dysregulated pathways in IBD patients. Finally, integration of activated macrophages offers a first-step towards a multi-factorial amenable IBD platform that could be scaled up to assess compound efficacy at early stages of drug development or in personalized medicine.

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Human Intestinal Enteroids Model MHC-II in the Gut Epithelium

Cited by 28 publications

References 35 publications

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells

Why do intestinal epithelial cells express MHC class II?

Development of a human primary gut-on-a-chip to model inflammatory processes

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