Forkhead Box Protein O1; Forkhead Transcription Factors; Foxo1 protein, mouse; Foxp3 protein, mouse; Receptors, Antigen, T-Cell; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Ptpn2 protein, mouse; Animals; Blotting, Western; CD4-Positive T-Lymphocytes/metabolism; Cells, Cultured; Female; Flow Cytometry; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Male; Mice; Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism; Receptors, Antigen, T-Cell/genetics; Receptors, Antigen, T-Cell/metabolism; T-Lymphocytes, Regulatory/metabolism; CD4-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Abstract :
[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Bothur, Evita; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Raifer, Hartmann; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Haftmann, Claudia; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany
Stittrich, Anna-Barbara; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany
Brüstle, Anne; The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia ; Experimental and Molecular Immunology, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Bollig, Nadine; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Bieringer, Maria; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Kang, Chol-Ho; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Reinhard, Katharina; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Camara, Bärbel; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Huber, Magdalena; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Visekruna, Alexander ; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Steinhoff, Ulrich ; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
Repenning, Antje; Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany
Bauer, Uta-Maria; Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany
Sexl, Veronika; Institute for Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Wien, Austria
Radbruch, Andreas; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany
Sparwasser, Tim; Institute of Infection Immunology, TWINCORE, Feodor-Lynen-Straße 7, 30625 Hannover, Germany
Mashreghi, Mir-Farzin; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany
Wah Mak, Tak; The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia
Lohoff, Michael; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany
We thank David Fruman for provision of the FOXO1(A3)-plasmid. This work was supported by Deutsche Forschungsgemeinschaft (GRK-767 and SFB/TR22 to M.L. and grant HU 1824/2-1 to M.H.) and Behring-Röntgen-Stiftung to M.L. and to M.H. A.R. has been supported by the ERC Advanced Grant (ERC-2010-AdG_20100317 Grant 268987) and M.F.M. was supported by the ‘e:Bio—Innovationswettbewerb Systembiologie’ program of the Federal Ministry of Education. D.B. is supported by the ATTRACT (consolidator) Programme of the National Research Fund Luxembourg (FNR).
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