NDLI: TGF-β-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORγt function

Content Provider	PubMed Central
Author	Zhou, Liang Lopes, Jared E. Chong, Mark M. W. Ivanov, Ivaylo I. Min, Roy Victora, Gabriel D. Shen, Yuelei Du, Jianguang Rubtsov, Yuri P. Rudensky, Alexander Y. Ziegler, Steven F. Littman, Dan R.
Abstract	T helper cells that produce IL-17 (Th17 cells) promote autoimmunity in mice and have been implicated in pathogenesis of human inflammatory diseases. At mucosal surfaces Th17 cells are thought to protect the host from infection while regulatory T (Treg) cells control immune responses and inflammation triggered by the resident microflora1–5. Differentiation of both cell types requires TGF-β, but depends on distinct transcription factors, RORγt for Th17 and Foxp3 for Treg cells6-8. How TGF-β regulates the differentiation of T cells with opposing activities has been perplexing. Here, we demonstrate that together with pro-inflammatory cytokines TGF-β orchestrates Th17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-β synergizes with IL-6 and IL-21 (ref. 9-11) to promote IL-23R expression, favoring Th17 cell differentiation. High concentrations of TGF-β repress IL-23R expression and favor Foxp3+ Treg cells. RORγt and Foxp3 are co-expressed in naïve CD4+ T cells exposed to TGF-β and in a subset of T cells in the small intestinal lamina propria (LP). In vitro, TGF-β-induced Foxp3 inhibits RORγt function at least in part through their interaction. Accordingly, LP T cells that co-express both transcription factors produce less IL-17 than those that express RORγt alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORγt, thereby promoting Th17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into Th17 or Treg cells depends upon the cytokine-regulated balance of RORγt and Foxp3.
Related Links	http://dx.doi.org/10.1038/nature06878
Ending Page	240
Page Count	5
Starting Page	236
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7192
Volume Number	453
Language	English
Publisher Date	2008-05-08
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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Jagged-1 signaling suppresses the IL-6 and TGF-β treatment-induced Th17 cell differentiation via the reduction of RORγt/IL-17A/IL-17F/IL-23a/IL-12rb1

Fyn promotes TH17 differentiation by regulating the kinetics of RORγt and Foxp3 expression1

Jagged-1 signaling suppresses the IL-6 and TGF-β treatment-induced Th17 cell differentiation via the reduction of RORγt/IL-17A/IL-17F/IL-23a/IL-12rb1

Estradiol Inhibits Th17 Cell Differentiation through Inhibition of RORγT Transcription by Recruiting ERα/REA Complex to the EREs of RORγT Promoter1

IL-21 and TGF-β are required for differentiation of human TH17 cells

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Interleukin 4 inhibits TGF-β-induced-Foxp3+T cells and generates, in combination with TGF-β, Foxp3− effector T cells that produce interleukins 9 and 10

Ursolic acid inhibits Th17 cell differentiation via STAT3/RORγt pathway and suppresses Schwann cell-mediated Th17 cell migration by reducing CXCL9/10 expression

IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells

TGF-β-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORγt function

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