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

Evita Bothur, Hartmann Raifer, Claudia Haftmann, Anna-Barbara Stittrich, Anne Brüstle, Dirk Brenner, Nadine Bollig, Maria Bieringer, Chol-Ho Kang, Katharina Reinhard, Bärbel Camara, Magdalena Huber, Alexander Visekruna, Ulrich Steinhoff, Antje Repenning, Uta-Maria Bauer, Veronika Sexl, Andreas Radbruch, Tim Sparwasser, Mir-Farzin Mashreghi, Tak Wah Mak and Michael Lohoff ()
Additional contact information
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9576

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