Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8

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https://doi.org/10.1053/j.gastro.2011.06.057
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Animals, Antigens, CD, Cells, Cultured, Dendritic Cells, Forkhead Transcription Factors, Homeostasis, Immune System, In Vitro Techniques, Integrin alpha Chains, Integrins, Intestines, Mice, Mice, Knockout, Models, Animal, Ovalbumin, T-Lymphocytes, Regulatory, Transforming Growth Factor beta, Tretinoin

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Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8. / Worthington, John J.; Czajkowska, Beata I.; Melton, Andrew C. et al.
In: Gastroenterology, Vol. 141, No. 5, 11.2011, p. 1802-1812.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Bibtex

@article{8b649fb9431a45bfb08e3ef3c79870df,

title = "Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8",

abstract = "BACKGROUND & AIMS: The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis.METHODS: Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured.RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3(+) Tregs in vitro and in vivo.CONCLUSIONS: CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.",

keywords = "Animals, Antigens, CD, Cells, Cultured, Dendritic Cells, Forkhead Transcription Factors, Homeostasis, Immune System, In Vitro Techniques, Integrin alpha Chains, Integrins, Intestines, Mice, Mice, Knockout, Models, Animal, Ovalbumin, T-Lymphocytes, Regulatory, Transforming Growth Factor beta, Tretinoin",

author = "Worthington, {John J.} and Czajkowska, {Beata I.} and Melton, {Andrew C.} and Travis, {Mark A.}",

note = "Open Access funded by Wellcome Trust {\textcopyright} 2011 by the AGA Institute",

year = "2011",

month = nov,

doi = "10.1053/j.gastro.2011.06.057",

language = "English",

volume = "141",

pages = "1802--1812",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "5",

}

RIS

TY - JOUR

T1 - Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8

AU - Worthington, John J.

AU - Czajkowska, Beata I.

AU - Melton, Andrew C.

AU - Travis, Mark A.

PY - 2011/11

Y1 - 2011/11

N2 - BACKGROUND & AIMS: The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis.METHODS: Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured.RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3(+) Tregs in vitro and in vivo.CONCLUSIONS: CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.

AB - BACKGROUND & AIMS: The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis.METHODS: Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured.RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3(+) Tregs in vitro and in vivo.CONCLUSIONS: CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.

KW - Animals

KW - Antigens, CD

KW - Cells, Cultured

KW - Dendritic Cells

KW - Forkhead Transcription Factors

KW - Homeostasis

KW - Immune System

KW - In Vitro Techniques

KW - Integrin alpha Chains

KW - Integrins

KW - Intestines

KW - Mice

KW - Mice, Knockout

KW - Models, Animal

KW - Ovalbumin

KW - T-Lymphocytes, Regulatory

KW - Transforming Growth Factor beta

KW - Tretinoin

U2 - 10.1053/j.gastro.2011.06.057

DO - 10.1053/j.gastro.2011.06.057

M3 - Journal article

C2 - 21723222

VL - 141

SP - 1802

EP - 1812

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -

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