Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine

McDole, Jeremiah; Wheeler, Leroy W.; McDonald, Keely G.; Wang, Baomei; Konjufca, Vjollca; Knoop, Kathryn A.; Newberry, Rodney D.; Miller, Mark J.

doi:10.1038/nature10863

Cited by 810 publications

(763 citation statements)

References 31 publications

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“…Loss of proper mucin secretion may directly lead to chronic inflammation, as it has been shown that MUC2 deficient mice spontaneously develop chronic colitis [43]. Besides mucin production, goblet cells secretes cytokines such as IL-7 [44] and thus may exert immunoregulatory functions, and can also deliver luminal antigens to the underlying DCs [45]. Recent studies have shown that a newly identified Clchannel, bestrophin2 (BEST2), is expressed specifically by colonic goblet cells [46,47].…”

Section: Role Of Iecs In the Pathogenesis Of Ibdmentioning

confidence: 99%

“…Also, several cytokines that are produced by the proinflammatory lymphocytes, such as IL-1b or IL-6, may b Goblet cells produce MUC2 or TFF3 and maintain the mucosal layer to sequester gut microbes from the surface of the epithelial layer [39]. Expression of specific ion channels such as Bestrophin2 may support the proper function of the mucus layer [44,45]. Goblet cells can also interact with the lamina propria immune cells through antigen delivery or cytokine production [42,43].…”

Section: Mechanism Of Epithelial Repair In Ibdmentioning

confidence: 99%

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Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Section: Role Of Iecs In the Pathogenesis Of Ibdmentioning

confidence: 99%

Section: Mechanism Of Epithelial Repair In Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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“…Two cyclic displayed peptides dominated the selection, 13C and 28PP, representing 36 of 40 clones sequenced. given a selection of library phage clones in the presence of 2x10 4 fold excess of wild type phage.…”

Section: In Vivo Validation For Specificity Of the Selected Peptide Pmentioning

confidence: 99%

Identification of Targeting Peptides for Mucosal Delivery in Sheep and Mice

et al. 2015

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In this study we identified and characterized a novel cyclic peptide that facilitates the rapid transportation of conjugated molecules across the epithelial layer of the small intestine. The peptide was initially selected from phage display libraries using a large animal experimental model which employed consecutive in vitro and in vivo panning. The procedure was designed to enrich for peptides that facilitated transcytosis across the intestinal epithelium into the intestinal afferent lymphatic system. A small set of peptides was repeatedly isolated using this selection method, 2 however the cyclic nonamer CTANSSAQC, 13C dominated. The activity of the putative targeting peptide C13 was then verified using a mouse model. These experiments showed that the 13C peptide as well as macromolecules conjugated to it were rapidly transported across the intestinal mucosa into distinct subsets of epithelial cells and CD11+ cells located in the lamina propria and Peyer's Patches. Significant amounts of intact protein could be delivered into the systemic circulation after rectal and nasal application. Thus, peptide 13C is regarded as an attractive carrier candidate for mucosal delivery of large molecules. The preferential targeting to distinct intestinal cells may be utilized to deliver active biological drugs for the effective control of diseases of the gut.

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“…A certain population of these activated T cells moves from the PPs to MLNs through draining lymphatic ducts, then into the bloodstream through the thoracic duct, and finally accumulates in the intestinal mucosa (11,18). In contrast, lamina propriaderived CD103 + dendritic cells bearing luminal Ags captured in the intestine (19)(20)(21) migrate into MLNs (22,23), where they activate and induce a 4 b 7 expression on T N cells (24)(25)(26). Guttropic T cells generated in MLNs collect in the intestine via recirculation (11).…”

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confidence: 99%

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

Kawabe

Sun

Fujita

et al. 2013

The Journal of Immunology

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Homeostatic proliferation of naive T cells in the spleen and cutaneous lymph nodes supplies memory–phenotype T cells. The “systemic” proliferative responses divide distinctly into fast or slow cell division rates. The fast proliferation is critical for generation of effector memory T cells. Because effector memory T cells are abundant in the lamina propria of the intestinal tissue, “gut-specific” homeostatic proliferation of naive T cells may be important for generation of intestinal effector memory T cells. However, such organ-specific homeostatic proliferation of naive T cells has not yet been addressed. In this study, we examined the gut-specific homeostatic proliferation by transferring CFSE-labeled naive CD4+ T cells into sublethally irradiated mice and separately evaluating donor cell division and differentiation in the intestine, mesenteric lymph nodes (MLNs), and other lymphoid organs. We found that the fast-proliferating cell population in the intestine and MLNs had a gut-tropic α4β7+ Th17 phenotype and that their production was dependent on the presence of commensal bacteria and OX40 costimulation. Mesenteric lymphadenectomy significantly reduced the Th17 cell population in the host intestine. Furthermore, FTY720 treatment induced the accumulation of α4β7+IL-17A+ fast-dividing cells in MLNs and eliminated donor cells in the intestine, suggesting that MLNs rather than intestinal tissues are essential for generating intestinal Th17 cells. These results reveal that MLNs play a central role in inducing gut-tropic Th17 cells and in maintaining CD4+ T cell homeostasis in the small intestine.

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Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine

Cited by 810 publications

References 31 publications

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Identification of Targeting Peptides for Mucosal Delivery in Sheep and Mice

Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

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