Faculty Opinions recommendation of Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.

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The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells

Scientific Reports ◽

10.1038/s41598-020-79122-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cristian Doñas ◽

Jocelyn Neira ◽

Francisco Osorio-Barrios ◽

Macarena Carrasco ◽

Dominique Fernández ◽

...

Keyword(s):

Dendritic Cells ◽

Retinoic Acid ◽

De Novo ◽

Histone Demethylase ◽

T Helper ◽

De Novo Synthesis ◽

T Helper 1 ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Lineage Stability

AbstractDendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients.

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Skin-draining lymph nodes contain dermis-derived CD103− dendritic cells that constitutively produce retinoic acid and induce Foxp3+ regulatory T cells

Blood ◽

10.1182/blood-2009-09-245274 ◽

2010 ◽

Vol 115 (10) ◽

pp. 1958-1968 ◽

Cited By ~ 222

Author(s):

Martin Guilliams ◽

Karine Crozat ◽

Sandrine Henri ◽

Samira Tamoutounour ◽

Pierre Grenot ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Retinoic Acid ◽

Regulatory T Cells ◽

Lymph Nodes ◽

De Novo ◽

Aldh Activity ◽

Mouse Tissues ◽

Environmental Interfaces ◽

Draining Lymph Nodes

Abstract Small intestinal CD103+ dendritic cells (DCs) have the selective ability to promote de novo generation of regulatory T cells via the production of retinoic acid (RA). Considering that aldehyde dehydrogenase (ALDH) activity controls the production of RA, we used a flow cytometry–based assay to measure ALDH activity at the single-cell level and to perform a comprehensive analysis of the RA-producing DC populations present in lymphoid and nonlymphoid mouse tissues. RA-producing DCs were primarily of the tissue-derived, migratory DC subtype and can be readily found in the skin and in the lungs as well as in their corresponding draining lymph nodes. The RA-producing skin-derived DCs were capable of triggering the generation of regulatory T cells, a finding demonstrating that the presence of RA-producing, tolerogenic DCs is not restricted to the intestinal tract as previously thought. Unexpectedly, the production of RA by skin DCs was restricted to CD103− DCs, indicating that CD103 expression does not constitute a “universal” marker for RA-producing mouse DCs. Finally, Toll-like receptor (TLR) triggering or the presence of a commensal microflora was not essential for the induction of ALDH activity in the discrete ALDH+ DC subsets that characterize tissues constituting environmental interfaces.

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Isolation and Functional Analysis of Lamina Propria Dendritic Cells from the Mouse Small Intestine

Methods in Molecular Biology - Gastrointestinal Physiology and Diseases ◽

10.1007/978-1-4939-3603-8_17 ◽

2016 ◽

pp. 181-188

Author(s):

Naoki Takemura ◽

Satoshi Uematsu

Keyword(s):

Functional Analysis ◽

Dendritic Cells ◽

Small Intestine ◽

Lamina Propria ◽

Mouse Small Intestine

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The protease phenotype and crystalline nature of the granules of intraepithelial mast cells in Trichinella spiralis-infected mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140464 ◽

1995 ◽

Vol 53 ◽

pp. 818-819

Author(s):

D.S. Friend ◽

N. Ghildyal ◽

M.F. Gurish ◽

K.F. Austen ◽

R.L. Stevens

Keyword(s):

Small Intestine ◽

Mast Cells ◽

Epithelial Cells ◽

Lamina Propria ◽

Trichinella Spiralis ◽

Intestinal Epithelial ◽

Carboxypeptidase A ◽

C3h Mice ◽

Granule Morphology ◽

Crystalline Nature

Trichinella spiralis induces a profound mastocytosis and eosinophilia in the small intestine of the infected mouse. Mouse mast cells (MC) store in their granules various combinations of at least five chymotryptic chymases [designated mouse MC protease (mMCP) 1 to 5], two tryptic proteases designated mMCP-6 and mMCP-7 and an exopeptidase, carboxypeptidase A (mMC-CPA). Using antipeptide, protease -specific antibodies to these MC granule proteases, immunohistochemistry was done to determine the distribution, number and protease phenotype of the MCs in the small intestine and spleen 10 to >60 days after Trichinella infection of BALB/c and C3H mice. TEM was performed to evaluate the granule morphology of the MCs between intestinal epithelial cells and in the lamina propria (mucosal MCs) and in the submucosa, muscle and serosa of the intestine (submucosal MCs).As noted in the table below, the number of submucosal MCs remained constant throughout the study. In contrast, on day 14, the number of MCs in the mucosa increased ~25 fold. Increased numbers of MCs were observed between epithelial cells in the mucosal crypts, in the lamina propria and to a lesser extent, between epithelial cells of the intestinal villi.

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