RANKL Is Necessary and Sufficient to Initiate Development of Antigen-Sampling M Cells in the Intestinal Epithelium

Knoop, Kathryn A.; Kumar, Nachiket; Butler, Betsy R.; Sakthivel, Senthilkumar K.; Taylor, Roger R.; Nochi, Tomonori; Akiba, Hisaya; Yagita, Hideo; Kiyono, Hiroshi; Williams, Ifor R.

doi:10.4049/jimmunol.0901563

Cited by 270 publications

(333 citation statements)

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“…To determine whether the altered pattern of stromal cell antigen expression in the small intestinal CPs of RANKL Ϫ/Ϫ mice could be corrected by providing an exogenous source of RANKL, RANKL Ϫ/Ϫ mice were treated with 100 g of GST-RANKL for 5 days. Although this treatment was previously shown to be sufficient to restore M cell differentiation in the PPs of RANKL Ϫ/Ϫ mice, 18 it failed to normalize stromal cell antigen expression in the small intestinal CPs or bring about recruitment of B cells into the CPs (data not shown).…”

Section: Stromal Cells In Small Intestinal Cps From Rankl ϫ/ϫ Mice Famentioning

confidence: 87%

“…Intestinal PPs are present in RANKL Ϫ/Ϫ mice, although they are smaller and exhibit a profound deficiency in the formation of M cells. 18 The contribution of RANKL to the development of the organized lymphoid tissues of the intestine that develop postnatally (ie, CPs and ILFs) has not been previously examined.…”

Section: Discussionmentioning

confidence: 99%

“…36 Although RANKL Ϫ/Ϫ mice are normally colonized by gut commensals, we previously showed they have less than 2% of the normal number of antigen-sampling M cells compared to wild-type mice. 18 This profound M cell deficit in RANKL Ϫ/Ϫ mice likely results in decreased antigen-sampling of the commensal flora, thereby impairing the NOD1-initiated differentiation of CPs into immature ILFs. Follicular dendritic cells isolated from PP have the capacity to respond directly to environmental stimuli, including retinoic acid and intestinal bacteria, by increasing production of both CXCL13 and BAFF, 37 indicating that stromal cells are able to directly sense the presence of the commensal enteric flora.…”

Section: Discussionmentioning

confidence: 99%

“…18 The GST-RANKL fusion protein was administered to RANKL null mice by initial i.p. and s.c. injections of 100 g of GST-RANKL followed by s.c. injections of 100 g per day for the next 4 days.…”

Section: Recombinant Mouse Ranklmentioning

confidence: 99%

“…We previously showed that differentiation of M cells in the PP FAE requires RANKL. 18 The Density and Distribution of CD11c ϩ Cells Are Not Perturbed in RANKL Ϫ/Ϫ CP CD11c ϩ dendritic cells account for 20% to 30% of the cells in the small intestinal CP of adult mice. 7 These CD11c ϩ cells are concentrated at the border of CPs, with the Thy-1 ϩ LTi cells predominating centrally.…”

Section: Rankl ϫ/ϫ Mice Develop Colonic Aggregates That Include B-celmentioning

confidence: 99%

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Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

Knoop

Butler

Kumar

et al. 2011

The American Journal of Pathology

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Cryptopatches (CPs) and isolated lymphoid follicles (ILFs) are organized intestinal lymphoid tissues that develop postnatally in mice and include stromal cells expressing the receptor activator of nuclear factor kappa-B ligand (RANKL). We investigated how stromal RANKL influences the development and differentiation of CPs and ILFs by analyzing the development of these lymphoid structures in knockout mice lacking RANKL. We found that RANKL ؊/؊ mice had a fourfold reduction in the overall density of CPs in the small intestine compared to control mice, with the largest decrease in the proximal small intestine. No B cells were present in CPs from the small intestine of RANKL ؊/؊ mice and ILF formation was completely blocked. In sharp contrast, colonic ILFs containing B cells were present in RANKL ؊/؊ mice. Stromal cells within CPs in the small intestine of RANKL ؊/؊ mice did not express CXCL13 (originally called B lymphocyte chemoattractant) and often lacked other normally expressed stromal cell antigens, whereas colonic lymphoid aggregates in RANKL ؊/؊ mice retained stromal CXCL13 expression. The CXCL13-dependent maturation of precursor CPs into ILFs is differentially regulated in the small intestine and colon, with an absolute requirement for RANKL only in the small intestine.

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Section: Stromal Cells In Small Intestinal Cps From Rankl ϫ/ϫ Mice Famentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Recombinant Mouse Ranklmentioning

confidence: 99%

Section: Rankl ϫ/ϫ Mice Develop Colonic Aggregates That Include B-celmentioning

confidence: 99%

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Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

Knoop

Butler

Kumar

et al. 2011

The American Journal of Pathology

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M Cells

Mabbott

Sehgal

Donaldson

2015

Encyclopedia of Life Sciences

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The mucosal immune system in the gastrointestinal tract helps protect against orally acquired pathogens. To efficiently do this, the mucosal immune system must be able to sample the gut lumenal contents to enable it to generate protective immune responses against pathogens. The transport of luminal antigens across mucosal epithelia is a key initial step in the induction of an efficient mucosal immune response. Here, we discuss how a unique population of epithelial cells termed M cells (or ‘microfold’ cells) enables the mucosal immune system to efficiently sample the intestinal contents. We describe the characteristic features of M cells; describe the molecular and cellular factors that influence their differentiation and functional maturation; discuss how lumenal antigens are sampled by M cells and also how the specific targeting of antigens to M cells may represent a novel method to induce antigen‐specific mucosal immunity. Key Concepts The mucosal immune system in the gastrointestinal and respiratory tracts acts to protect against pathogens acquired by ingestion and inhalation, respectively. The transport of luminal antigens across mucosal epithelia is a key initial step in the induction of an efficient mucosal immune response. M cells are a unique population of epithelial cells which are specialised for the transcytosis of a broad range of materials such as particulate antigens, soluble macromolecules, pathogens and secretory IgA across the gut epithelium into the gut‐associated lymphoid tissues. The efficient transcytosis of antigens by M cells is an important first step in the induction of efficient mucosal immune responses to certain pathogenic microorganisms. M cells derive from Lgr5 + stem cells in the intestinal crypts. Stimulation via the cytokine RANKL and the subsequent intrinsic expression of distinct transcription factors specifically trigger the differentiation of the Lgr5 + stem‐cell‐derived proliferative daughter cells into mature, functional M cells. The sampling of lumenal antigens by M cells may occur in a nonselective manner (e.g. via constitutive micropinocytosis). However, M cells also appear to express a range of ‘immunosurveillance’ receptors suggesting that some antigens are acquired specifically via receptor‐mediated endocytosis. The specific targeting of vaccine antigens may represent novel strategies to develop mucosal vaccines and induce mucosal immunity. Aging has a dramatic influence on the functional maturation of M cells.

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Recent Advances in Cell‐Based In Vitro Models to Recreate Human Intestinal Inflammation

Macedo,

Dias Neto,

Pastrana

et al. 2023

Advanced Science

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Inflammatory bowel disease causes a major burden to patients and healthcare systems, raising the need to develop effective therapies. Technological advances in cell culture, allied with ethical issues, have propelled in vitro models as essential tools to study disease aetiology, its progression, and possible therapies. Several cell‐based in vitro models of intestinal inflammation have been used, varying in their complexity and methodology to induce inflammation. Immortalized cell lines are extensively used due to their long‐term survival, in contrast to primary cultures that are short‐lived but patient‐specific. Recently, organoids and organ‐chips have demonstrated great potential by being physiologically more relevant. This review aims to shed light on the intricate nature of intestinal inflammation and cover recent works that report cell‐based in vitro models of human intestinal inflammation, encompassing diverse approaches and outcomes.

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RANKL Is Necessary and Sufficient to Initiate Development of Antigen-Sampling M Cells in the Intestinal Epithelium

Cited by 270 publications

References 47 publications

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

M Cells

Recent Advances in Cell‐Based In Vitro Models to Recreate Human Intestinal Inflammation

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