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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

Author

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  • Estelle Bettelli

    (Center for Neurologic Diseases, Brigham and Women's Hospital)

  • Yijun Carrier

    (Center for Neurologic Diseases, Brigham and Women's Hospital)

  • Wenda Gao

    (Transplant Research Center, Beth Israel Hospital, Harvard Medical School)

  • Thomas Korn

    (Center for Neurologic Diseases, Brigham and Women's Hospital)

  • Terry B. Strom

    (Transplant Research Center, Beth Israel Hospital, Harvard Medical School)

  • Mohamed Oukka

    (Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School)

  • Howard L. Weiner

    (Center for Neurologic Diseases, Brigham and Women's Hospital)

  • Vijay K. Kuchroo

    (Center for Neurologic Diseases, Brigham and Women's Hospital)

Abstract

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms1,2. Recently, a subset of interleukin (IL)-17-producing T (TH17) cells distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury3,4,5. In contrast, CD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury6. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of Treg cells7. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation8,9, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of TH17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic TH17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Suggested Citation

  • Estelle Bettelli & Yijun Carrier & Wenda Gao & Thomas Korn & Terry B. Strom & Mohamed Oukka & Howard L. Weiner & Vijay K. Kuchroo, 2006. "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, Nature, vol. 441(7090), pages 235-238, May.
    • Handle: RePEc:nat:nature:v:441:y:2006:i:7090:d:10.1038_nature04753
    DOI: 10.1038/nature04753
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    Cited by:

    1. Moritz Muckenhuber & Konstantinos Mengrelis & Anna Marianne Weijler & Romy Steiner & Verena Kainz & Marlena Buresch & Heinz Regele & Sophia Derdak & Anna Kubetz & Thomas Wekerle, 2024. "IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Manuel A. Podestà & Cecilia B. Cavazzoni & Benjamin L. Hanson & Elsa D. Bechu & Garyfallia Ralli & Rachel L. Clement & Hengcheng Zhang & Pragya Chandrakar & Jeong-Mi Lee & Tamara Reyes-Robles & Reza A, 2023. "Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Agnieszka Strzelak & Aleksandra Ratajczak & Aleksander Adamiec & Wojciech Feleszko, 2018. "Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review," IJERPH, MDPI, vol. 15(5), pages 1-35, May.
    4. Tian Hong & Jianhua Xing & Liwu Li & John J Tyson, 2011. "A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells," PLOS Computational Biology, Public Library of Science, vol. 7(7), pages 1-13, July.
    5. Benjamin P. Hurrell & Doumet Georges Helou & Emily Howard & Jacob D. Painter & Pedram Shafiei-Jahani & Arlene H. Sharpe & Omid Akbari, 2022. "PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Sina Riemschneider & Maximilian Hoffmann & Ulla Slanina & Klaus Weber & Sunna Hauschildt & Jörg Lehmann, 2021. "Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms," IJERPH, MDPI, vol. 18(5), pages 1-17, February.

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