Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium

Intestinal epithelial cells (IECs) absorb nutrients, respond to microbes, provide barrier function and help coordinate immune responses. We profiled 53,193 individual epithelial cells from mouse small intestine and organoids, and characterized novel subtypes and their gene signatures. We showed unexpected diversity of hormone-secreting enteroendocrine cells and constructed their novel taxonomy. We distinguished between two tuft cell subtypes, one of which expresses the epithelial cytokine TSLP and CD45 (Ptprc), the pan-immune marker not previously associated with non-hematopoietic cells. We also characterized how cell-intrinsic states and cell proportions respond to bacterial and helminth infections. Salmonella infection caused an increase in Paneth cells and enterocytes abundance, and broad activation of an antimicrobial program. In contrast, Heligmosomoides polygyrus caused an expansion of goblet and tuft cell populations. Our survey highlights new markers and programs, associates sensory molecules to cell types, and uncovers principles of gut homeostasis and response to pathogens.

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“…Since M cells represent only about 10% of this rare structure 36 , they were not detected in our initial survey, as expected.…”

Section: Resultssupporting

confidence: 69%

A single-cell survey of the small intestinal epithelium

Haber

Biton

Rogel

et al. 2017

Nature

1,416

117

1,795

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“…We have shown direct interaction between the S. flexneri type 2a polysaccharide and GP2 on M cells in human ileum tissue sections. GP2 is a heavily glycosylated protein that is an established marker for M cells (47). Before the use of the GP2 antibody, this protein was identified on M cells with UEA-1, a lectin with specificity for the α1-2-linked fucose structures found in the blood group antigens on this glycoprotein (33,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

“…GP2 is a heavily glycosylated protein that is an established marker for M cells (47). Before the use of the GP2 antibody, this protein was identified on M cells with UEA-1, a lectin with specificity for the α1-2-linked fucose structures found in the blood group antigens on this glycoprotein (33,(47)(48)(49). The interaction of S. flexneri polysaccharide with GP2 provides further evidence for a polysaccharide-dependent adherence mechanism for S. flexneri that is likely to involve binding to host glycoconjugates identified in our array screen and confirmed with SPR.…”

Section: Discussionmentioning

confidence: 99%

Glycan:glycan interactions: High affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells

Day

Tran

Semchenko

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

104

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Cells from all domains of life express glycan structures attached to lipids and proteins on their surface, called glycoconjugates. Cell-tocell contact mediated by glycan:glycan interactions have been considered to be low-affinity interactions that precede highaffinity protein-glycan or protein-protein interactions. In several pathogenic bacteria, truncation of surface glycans, lipooligosaccharide (LOS), or lipopolysaccharide (LPS) have been reported to significantly reduce bacterial adherence to host cells. Here, we show that the saccharide component of LOS/LPS have direct, high-affinity interactions with host glycans. Glycan microarrays reveal that LOS/LPS of four distinct bacterial pathogens bind to numerous host glycan structures. Surface plasmon resonance was used to determine the affinity of these interactions and revealed 66 high-affinity host-glycan:bacterial-glycan pairs with equilibrium dissociation constants (K D ) ranging between 100 nM and 50 μM. These glycan:glycan affinity values are similar to those reported for lectins or antibodies with glycans. Cell assays demonstrated that glycan:glycan interaction-mediated bacterial adherence could be competitively inhibited by either host cell or bacterial glycans. This is the first report to our knowledge of high affinity glycan:glycan interactions between bacterial pathogens and the host. The discovery of large numbers of glycan:glycan interactions between a diverse range of structures suggests that these interactions may be important in all biological systems.H ost surface glycosylation is ubiquitous and is targeted by pathogenic bacteria, viruses, fungi and parasites for adherence and toxin binding and by glycosidases (1). Escherichia coli type 1 fimbriae, FimH, is one of the most widely studied glycanrecognizing protein adhesins, with specificity for monomannose to oligomannose structures with the variability of the mannose structure bound leading to different tissue tropism (2). Other glycan-recognizing adhesins expressed by bacteria include the following: Pseudomonas aeruginosa lectins 1 and 2 (PA-IL and PA-IIL) that have specificity for galactose and fucose, respectively (3); Helicobacter pylori SabA, specific for sialic acid containing glycoconjugates including sialyLewis X; and BabAspecific for fucosylated glycoconjugates including Lewis B (4, 5). Although there are numerous known glycan binding adhesins, the adhesins of some bacteria that interact with host surface glycans remain unknown.Direct interactions between surface glycans (glycan:glycan interactions) have been reported in sea sponges as heterogenous glycan interactions, and in mouse embryo development and cancer where homodimers of Lewis X (LeX) or ganglioside structures play a role in cell adhesion and growth factor receptor interactions (6, 7). Outside of these reports, glycan:glycan interactions, when noted, have generally been considered to be low-affinity, weak interactions (8) that precede high-affinity protein:glycan or protein:protein interactions (1, 2, 5, 9).Interestingly, there...

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“…In addition, it is known that specific receptor-mediated binding of Ag to M cells enhances the transcytosis of luminal Ags [18]. We detected expression of FPR-2 on M cells, which were identified using the M-cell-specific Ab NKM 16-2-4, in sliced tissue sections prepared from PPs of the terminal ileum of a CX3CR1 +/GFP mouse (Fig.…”

Section: Ll-37 Receptor On M Cells May Play a Nonredundant Role In Enmentioning

confidence: 99%

Antimicrobial peptide LL‐37 promotes antigen‐specific immune responses in mice by enhancing Th17‐skewed mucosal and systemic immunities

et al. 2015

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The human antimicrobial peptide LL-37 is known to have chemotactic and modulatory activities on various cells including monocytes, T cells, and epithelial cells. Given that LL-37 enhances chemotactic attraction and modulates the activity of DCs, it is conceivablethat it might play a role as an immune adjuvant by skewing the immune environment toward immunostimulatory conditions. In this study, we characterized the mucosal adjuvant activity of LL-37 using model and pathogenic Ags. When LL-37-conjugated Ag was administered orally to mice, a tolerogenic Peyer's patch environment was altered to cell populations containing IL-6-secreting CD11c + , CD11c + CD70 + , and Th17 cells capable of evoking a subsequent LL-37-conjugated Ag-specific immune response in both systemic and mucosal immune compartments. In addition, we showed presentation of formyl peptide receptor, an LL-37 receptor, on M cells, which may aid the initiation of an LL-37-mediated enhanced immune response through targeting and transcytosis of the conjugated Ag. Based on our findings, we conclude that LL-37 has potential as an oral mucosal adjuvant, not only by enhancing the delivery of LL-37-conjugated Ag to M cells, but also by triggering T-cell-mediated Ag-specific immune responses through modulation of the mucosal immune environment.Keywords: Antimicrobial peptide r LL-37 r Mucosal immunity r Systemic immunity r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe mucosal surface is continuously exposed to microbiota, food antigens (Ags), and allergens [1]. To protect the body from foreign Correspondence: Dr. Yong-Suk Jang e-mail: yongsuk@jbnu.ac.kr Ags, the gastrointestinal mucosa coordinates a specialized immune system in which Peyer's patches (PPs) and mesenteric lymph nodes (MLNs) serve as mucosal immune inductive sites and the lamina propria (LP) serves as a mucosal effector site [2]. In the mucosal immune system, secretory immunoglobulin A (SIgA) plays a major defensive role by inhibiting pathogen adhesion and neutralizing viruses and toxins [3]. Production of SIgA can be achieved through both T-cell-independent and T-cell-dependent pathways in PPs.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1402-1413 Immunomodulation 1403 Production of SIgA by a T-cell-independent pathway is rapidly developed in response to Toll-like receptor (TLR) signaling or by inducing the expression of B-cell-activating factor belonging to the TNF family (BAFF) in innate immune cells, although this SIgA has low affinity [4]. In contrast, induction of IgA + -cell development by a T-cell-dependent pathway takes place in the germinal center (GC) and is orchestrated by follicular dendritic cells (FDCs). This process takes approximately 5 to 7 days and requires stimulation by cytokine signals, including TGF-β, . This T-cell-dependent GC pathway induces the development of highaffinity Ag-specific SIgA and isotype-switched memory cells, which in tu...

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Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium

Cited by 573 publications

References 112 publications

A single-cell survey of the small intestinal epithelium

A single-cell survey of the small intestinal epithelium

Glycan:glycan interactions: High affinity biomolecular interactions that can mediate binding of pathogenic bacteria to host cells

Antimicrobial peptide LL‐37 promotes antigen‐specific immune responses in mice by enhancing Th17‐skewed mucosal and systemic immunities

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