Human Gut-Specific Homeostatic Dendritic Cells Are Generated from Blood Precursors by the Gut Microenvironment

Mann, Elizabeth R.; Bernardo, David; Al-Hassi, Hafid O.; English, Nicholas R.; Clark, Susan; McCarthy, Neil E.; Milestone, Andrew N.; Cochrane, Stella; Hart, Ailsa; Stagg, Andrew J.; Knight, Stella C.

doi:10.1002/ibd.21893

Cited by 33 publications

(78 citation statements)

References 47 publications

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“…There was no difference in the percentage or type of circulating DC between HC (with not known autoimmune diseases or malignancies) and CD-GFD patients. In agreement with our previous findings circulating mDC from HC displayed a multi-homing β7 + CLA + phenotype (6). On the contrary, mDC from GFD-CD patients had decreased CLA expression ( Fig.…”

supporting

confidence: 93%

“…DC are therefore central in CD pathogenesis as they present gluten antigen to T-cells in a HLA-DQ2 restricted manner generating gluten-specific pro-inflammatory gut-homing T-cells (5). DC themselves also express homing markers displaying a multi-homing potential in the blood from healthy controls (HC) (6). However, the homing marker profile of blood DC is altered during gut inflammation.…”

mentioning

confidence: 99%

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Constitutive gut-homing capacity on circulating myeloid dendritic cells in coeliac disease

Comino

Šuligoj

Al-Hassi

et al. 2014

Rev. esp. enferm. dig.

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supporting

confidence: 93%

mentioning

confidence: 99%

Constitutive gut-homing capacity on circulating myeloid dendritic cells in coeliac disease

Comino

Šuligoj

Al-Hassi

et al. 2014

Rev. esp. enferm. dig.

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“…9C). Thus, stimulated (CFSE low ) T cells maintained the gut-homing β7 integrin and decreased expression of the skin-homing CLA, compared with unconditioned (basal) DCs as previously reported when using cultured SNs from healthy controls [26]. However, when DCs had been conditioned with inflamed areas from the same patients, DCs did not decrease their stimulatory capacity (Fig.…”

supporting

confidence: 81%

“…Thus, tolerogenic "gutlike" DCs can be generated when they are exposed to such microenvironments [22][23][24][25][26]. In UC patients, immune homeostasis in the gastrointestinal tract is compromised.…”

Section: Introductionmentioning

confidence: 99%

“…1A), assessing cytokine secretion by DCs is not a feasible approach. Therefore, we studied their natural ongoing intracellular cytokine production, in the absence of any external challenge [8,26], following conditioning with intestinal microenvironments.None of the assayed cytokines in the culture SNs correlated with the ongoing cytokine production of DCs following SN conditioning (data not shown). When exposed to a noninflamed microenvironment, DCs decreased ongoing production of proinflammatory cytokines IL-12 and IL-6, and increased regulatory cytokine IL-10, when compared with DCs exposed to paired inflamed areas (Fig.…”

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confidence: 99%

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IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

et al. 2012

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Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology.Keywords: Dendritic cells r IL-6 r Mucosal immunity r Intestinal immunity r Ulcerative colitis Correspondence: Prof. Stella C. Knight e-mail: s.knight@imperial.ac.uk IntroductionThe gastrointestinal tract is in contact with a wide variety of commensal microbiota and diverse pathogens, and therefore C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1338 David Bernardo et al. Eur. J. Immunol. 2012. 42: 1337-1353 requires a balance to be maintained between immunity and immune tolerance; the lack of immune responses against food antigens and/or the commensal microbiota is essential to maintain the homeostasis of the gastrointestinal tract [1]. Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), traditionally related to a Th2 cytokine profile mediated by 3], where immune homeostasis of the gastrointestinal tract is compromised. Up to 1/3rd of UC patients can develop extraintestinal manifestations with the skin being one of such tissues [4,5].Dendritic cells (DCs) are the most potent antigen presenting cells and determine the nature and type of immune responses [6,7]. Intestinal DCs control immune tolerance in the gastrointestinal tract [8][9][10]. DCs also maintain immune responses localized to specific tissues, since they imprint specific tissue-homing profiles on stimulated T cells [11]. Retinoic acid (RA), the active form of vitamin A following dehydrogenization by the RALDH2 enzyme controls some of the mechanisms of immune homeostasis of the gut [12][13][14]. RA-producing DCs mediate the IgA switching of B cells [15], the generation of T cells with a regulatory phenotype [10], and the imprinting of gut-homing markers on B and T cells [16,17], thereby keeping tolerogenic immune responses com...

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Altered human gut dendritic cell properties in ulcerative colitis are reversed by Lactobacillus plantarum extracellular encrypted peptide STp

Al-Hassi

Mann

Sánchez

et al. 2013

Molecular Nutrition Food Res

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Scope:The human/microbiota cross-talk is partially mediated by bacteria-derived peptides like Serine-Threonine peptide (STp), which is resistant to gut proteolysis, is found in the human healthy colon and induces regulatory properties on gut dendritic cells (DCs); here we characterized human gut DC in ulcerative colitis (UC) patients and studied the effect of STp on their properties. Methods and results: Human colonic DC from healthy controls and UC patients were isolated, conditioned for 24 h +/− STp and characterized by flow cytometry, immunohistochemistry, and electron microscopy. Expression of immature DC markers DC-SIGN and ILT3, and Tolllike receptors were increased on gut UC-DC. Langerin (involved in phagocytosis), lymph node homing marker CCR7, and activation markers CD40/CD80/CD86 were decreased in UC. Gut DC had restricted stimulatory capacity for T-cells in UC. Conditioning of DC with STp in vitro reduced Toll-like receptor expression, increased CD40 and CD80 expression, and restored their stimulatory capacity. Conclusion: Colonic DCs display an abnormal immature phenotype in UC, which was partially restored following STp treatment. Bacteria-derived metabolites, like STp, seem to have a role in gut homeostasis that is missing in UC so they might lead a new era of probiotic products setting the basis for nondrug dietary therapy in inflammatory bowel disease.

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Human Gut-Specific Homeostatic Dendritic Cells Are Generated from Blood Precursors by the Gut Microenvironment

Abstract: Tissue-specific factors manipulate immunity via modulating characteristics of DC and may provide tools to generate tissue-specific immunotherapy.

Cited by 33 publications

References 47 publications

Constitutive gut-homing capacity on circulating myeloid dendritic cells in coeliac disease

Constitutive gut-homing capacity on circulating myeloid dendritic cells in coeliac disease

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

Altered human gut dendritic cell properties in ulcerative colitis are reversed by Lactobacillus plantarum extracellular encrypted peptide STp

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