IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms9576.html
   My bibliography  Save this article

Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1

Author

Listed:
  • Evita Bothur

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Hartmann Raifer

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Claudia Haftmann

    (German Rheumatism Research Center Berlin)

  • Anna-Barbara Stittrich

    (German Rheumatism Research Center Berlin)

  • Anne Brüstle

    (The John Curtin School of Medical Research, The Australian National University)

  • Dirk Brenner

    (The John Curtin School of Medical Research, The Australian National University
    Experimental and Molecular Immunology, Luxembourg Institute of Health
    Odense Research Center for Anaphylaxis (ORCA), Odense University Hospital, University of Southern Denmark)

  • Nadine Bollig

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Maria Bieringer

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Chol-Ho Kang

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Katharina Reinhard

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Bärbel Camara

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Magdalena Huber

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Alexander Visekruna

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Ulrich Steinhoff

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

  • Antje Repenning

    (Institute of Molecular Biology and Tumor Research, University of Marburg)

  • Uta-Maria Bauer

    (Institute of Molecular Biology and Tumor Research, University of Marburg)

  • Veronika Sexl

    (Institute for Pharmacology and Toxicology, University of Veterinary Medicine Vienna)

  • Andreas Radbruch

    (German Rheumatism Research Center Berlin)

  • Tim Sparwasser

    (Institute of Infection Immunology, TWINCORE)

  • Mir-Farzin Mashreghi

    (German Rheumatism Research Center Berlin)

  • Tak Wah Mak

    (The John Curtin School of Medical Research, The Australian National University)

  • Michael Lohoff

    (Institute for Medical Microbiology and Hygiene, University of Marburg)

Abstract

Regulatory T-cells induced via IL-2 and TGFβ in vitro (iTreg) suppress immune cells and are potential therapeutics during autoimmunity. However, several reports described their re-differentiation into pathogenic cells in vivo and loss of their key functional transcription factor (TF) FOXP3 after T-cell antigen receptor (TCR)-signalling in vitro. Here, we show that TCR-activation antagonizes two necessary TFs for foxp3 gene transcription, which are themselves regulated by phosphorylation. Although the tyrosine phosphatase PTPN2 is induced to restrain IL-2-mediated phosphorylation of the TF STAT5, expression of the TF FOXO1 is downregulated and miR-182, a suppressor of FOXO1 expression, is upregulated. TGFβ counteracts the FOXP3-depleting TCR-signal by reassuring FOXO1 expression and by re-licensing STAT5 phosphorylation. Overexpressed phosphorylation-independent active versions of FOXO1 and STAT5 or knockdown of PTPN2 restores FOXP3 expression despite TCR-signal and absence of TGFβ. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.

Suggested Citation

  • Evita Bothur & Hartmann Raifer & Claudia Haftmann & Anna-Barbara Stittrich & Anne Brüstle & Dirk Brenner & Nadine Bollig & Maria Bieringer & Chol-Ho Kang & Katharina Reinhard & Bärbel Camara & Magdale, 2015. "Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9576
    DOI: 10.1038/ncomms9576
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms9576
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms9576?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9576. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.