title: Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1.
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.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Evita
authors.initials: E
authors.lastname: Bothur
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Hartmann
authors.initials: H
authors.lastname: Raifer
authors.affiliation: German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Haftmann
authors.affiliation: German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Anna-Barbara
authors.initials: AB
authors.lastname: Stittrich
authors.affiliation: The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bollig
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Bieringer
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Chol-Ho
authors.initials: CH
authors.lastname: Kang
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Reinhard
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Camara
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Huber
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Alexander
authors.identifier: http://orcid.org/0000-0002-5207-9545
authors.initials: A
authors.lastname: Visekruna
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steinhoff
authors.affiliation: Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Repenning
authors.affiliation: Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany.
authors.forename: Uta-Maria
authors.initials: UM
authors.lastname: Bauer
authors.affiliation: Institute for Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Wien, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Institute of Infection Immunology, TWINCORE, Feodor-Lynen-Straße 7, 30625 Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Mir-Farzin
authors.initials: MF
authors.lastname: Mashreghi
authors.affiliation: The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia.
authors.forename: Tak
authors.initials: T
authors.lastname: Wah Mak
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lohoff
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse
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