NDLI: Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells

Content Provider	PubMed Central
Author	Wei, Jun Omar, Duramad Perng, Olivia A. Reiner, Steven L. Liu, Yong-jun Qin, F. Xiao-feng
Copyright Year	2007
Abstract	Recent studies have highlighted the importance of peripheral induction of Foxp3-expressing regulatory T cells (Tregs) in the dominant control of immunological tolerance. However, Foxp3+ Treg differentiation from naïve CD4+ T cells occurs only under selective conditions, whereas the classical T helper (Th) 1 and 2 effector development often dominate T cell immune responses to antigen stimulation in the periphery. The reason for such disparity remains poorly understood. Here we report that Th1/Th2-polarizing cytokines can potently inhibit Foxp3+ Treg differentiation from naïve CD4+ precursors induced by TGF-β. Furthermore, antigen receptor-primed CD4+ T cells are resistant to Treg induction because of autocrine production of IFNγ and/or IL-4, whereas neutralizing IFNγ and IL-4 not only can potentiate TGF-β-mediated Foxp3 induction in vitro but can also enhance antigen-specific Foxp3+ Treg differentiation in vivo. Mechanistically, inhibition of Foxp3+ Treg development by Th1/Th2-polarizing cytokines involves the activation of Th1/Th2 lineage transcription factors T-bet and GATA-3 through the canonical Stat1-, Stat4-, and Stat6-dependent pathways. Using IFNγ and IL-4 knockouts and retrovirus-mediated transduction of T-bet and GATA-3, we further demonstrate that enforced expression of the Th1/Th2 lineage-specific transcription factors is sufficient to block Foxp3 induction and Treg differentiation independent of the polarizing/effector cytokines. Thus, our study has unraveled a previously unrecognized mechanism of negative cross-regulation of Foxp3+ Treg fate choice by Th1/Th2 lineage activities. In addition, these findings also provide an attainable explanation for the general paucity of antigen-triggered de novo generation of Foxp3+ Tregs in the periphery.
Related Links	http://dx.doi.org/10.1073/pnas.0703642104
Ending Page	18174
Page Count	6
Starting Page	18169
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	46
Volume Number	104
Language	English
Publisher	National Academy of Sciences
Publisher Date	2007-11-13
Access Restriction	Open
Rights Holder	National Academy of Sciences
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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