M cell-derived vesicles suggest a unique pathway for trans-epithelial antigen delivery

Sakhon, Olivia S.; Ross, Brittany N.; Gusti, Veronica; Pham, An Joseph; Vu, Kathy; Lo, David

doi:10.1080/21688370.2015.1004975

Cited by 38 publications

(27 citation statements)

References 46 publications

(47 reference statements)

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“…Antigens that are transcytosed by M cells are released into their basolateral pockets where they are sampled by lymphocytes and mononuclear phagocytes (MNP; a heterogeneous population of macrophages and classical dendritic cells; DC) [46–48]. The acquisition of prions by MNP such as CD11c + classical DC may mediate their initial transport to FDC [8, 16, 49], and the subsequent transfer of prions from FDC to the peripheral nervous system [50–52].…”

Section: Resultsmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

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Section: Resultsmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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“…The lack of particulate antigen uptake by subepithelial cDC (DN cDC2) in vivo is in agreement first with their low number in this region and second with in vitro microparticle uptake assays showing a much more efficient phagocytic activity of LysoDC and LysoMac as compared to dome cDC ( 40 , 42 ). Interestingly, in addition to transporting luminal antigens in their basolateral pocket or in the SED, M cells constitutively release on their basal side microvesicles, which are taken up by subepithelial CD11c + CD11b + CX 3 CR1 + cells, i.e., LysoDC and TIM-4 − LysoMac ( 54 ). Finally, monocyte-derived cells and M cell cooperation extend beyond cell death since the former engulf dying M cells (Table 2 ) ( 42 ).…”

Section: Functions Of Pp Phagocyte Subsetsmentioning

confidence: 99%

The Peyer’s Patch Mononuclear Phagocyte System at Steady State and during Infection

et al. 2017

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The gut represents a potential entry site for a wide range of pathogens including protozoa, bacteria, viruses, or fungi. Consequently, it is protected by one of the largest and most diversified population of immune cells of the body. Its surveillance requires the constant sampling of its encounters by dedicated sentinels composed of follicles and their associated epithelium located in specialized area. In the small intestine, Peyer’s patches (PPs) are the most important of these mucosal immune response inductive sites. Through several mechanisms including transcytosis by specialized epithelial cells called M-cells, access to the gut lumen is facilitated in PPs. Although antigen sampling is critical to the initiation of the mucosal immune response, pathogens have evolved strategies to take advantage of this permissive gateway to enter the host and disseminate. It is, therefore, critical to decipher the mechanisms that underlie both host defense and pathogen subversive strategies in order to develop new mucosal-based therapeutic approaches. Whereas penetration of pathogens through M cells has been well described, their fate once they have reached the subepithelial dome (SED) remains less well understood. Nevertheless, it is clear that the mononuclear phagocyte system (MPS) plays a critical role in handling these pathogens. MPS members, including both dendritic cells and macrophages, are indeed strongly enriched in the SED, interact with M cells, and are necessary for antigen presentation to immune effector cells. This review focuses on recent advances, which have allowed distinguishing the different PP mononuclear phagocyte subsets. It gives an overview of their diversity, specificity, location, and functions. Interaction of PP phagocytes with the microbiota and the follicle-associated epithelium as well as PP infection studies are described in the light of these new criteria of PP phagocyte identification. Finally, known alterations affecting the different phagocyte subsets during PP stimulation or infection are discussed.

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“…FAE differs from neighboring adjacent villous intestinal epithelium (VE) both structurally and by cell composition: within this cell layer, M cells (or microfold cells) are responsible for the translocation and presentation of antigens to immune cells (Onishi et al, 2007 ). M cells are abundantly distributed in FAE but not in VE and are able to transport antigens directly to the subepithelial lymphoid follicles (Sakhon et al, 2015 ) or to proceed and present antigens by using major histocompatibility complex (MHC) II (Allan et al, 1993 ). Moreover, FAE lacks the subepithelial myofibroblast sheath, the basal lamina of FAE is more porous compared to VE, and the basolateral surface of M cells is enhanced by invagination, promoting a faster translocation of antigens (Neutra et al, 2001 ; Takeuchi and Gonda, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of Barrier Properties in Follicle-Associated Epithelium of Porcine Peyer's Patches Reveals Major Sealing Function of Claudin-4

et al. 2017

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The pig represents a preferred model for the analysis of intestinal immunology. However, the barrier of the follicle-associated epithelium (FAE) covering porcine Peyer's patches (PP) has not yet been characterized in detail. This study aimed to perform this characterization in order to pave the way toward an understanding of the functional contribution of epithelial barrier properties in gut immunology. Porcine tissue specimens were taken from the distal small intestine in order to obtain electrophysiological data of PP FAE and neighboring villous epithelium (VE), employing the Ussing chamber technique. Transepithelial resistance (TER) and paracellular fluorescein flux were measured, and tissues were morphometrically compared. In selfsame tissues, expression and localization of major tight junction (TJ) proteins (claudin-1, -2, -3, -4, -5, and -8) were analyzed. PP FAE specimens showed a higher TER and a lower apparent permeability for sodium fluorescein than VE. Immunoblotting revealed an expression of all claudins within both epithelia, with markedly stronger expression of the sealing TJ protein claudin-4 in PP FAE compared with the neighboring VE. Immunohistochemistry confirmed the expression and localization of all claudins in both PP FAE and VE, with stronger claudin-4 abundance in PP FAE. The results are in accordance with the physiological function of the FAE, which strongly regulates and limits antigen uptake determining a mandatory transcellular route for antigen presentation, highlighting the importance of this structure for the first steps of the intestinal immune response. Thus, this study provides detailed insights into the specific barrier properties of the porcine FAE covering intestinal PP, at the interface of intestinal immunology and barriology.

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M cell-derived vesicles suggest a unique pathway for trans-epithelial antigen delivery

Cited by 38 publications

References 46 publications

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

The Peyer’s Patch Mononuclear Phagocyte System at Steady State and during Infection

Molecular Characterization of Barrier Properties in Follicle-Associated Epithelium of Porcine Peyer's Patches Reveals Major Sealing Function of Claudin-4

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