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Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1.
Bothur, Evita; Raifer, Hartmann; Haftmann, Claudia; Stittrich, Anna-Barbara; Brüstle, Anne; Brenner, Dirk; Bollig, Nadine; Bieringer, Maria; Kang, Chol-Ho; Reinhard, Katharina; Camara, Bärbel; Huber, Magdalena; Visekruna, Alexander; Steinhoff, Ulrich; Repenning, Antje; Bauer, Uta-Maria; Sexl, Veronika; Radbruch, Andreas; Sparwasser, Tim; Mashreghi, Mir-Farzin; Wah Mak, Tak; Lohoff, Michael.
Afiliación
  • Bothur E; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Raifer H; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Haftmann C; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • Stittrich AB; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • Brüstle A; The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia.
  • Brenner D; The John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra City, ACT 2600, Australia.
  • Bollig N; Experimental and Molecular Immunology, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg.
  • Bieringer M; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
  • Kang CH; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Reinhard K; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Camara B; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Huber M; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Visekruna A; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Steinhoff U; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Repenning A; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Bauer UM; Institute for Medical Microbiology and Hygiene, University of Marburg, Hans Meerwein Strasse 2, 35037 Marburg, Germany.
  • Sexl V; Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany.
  • Radbruch A; Institute of Molecular Biology and Tumor Research, University of Marburg, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany.
  • Sparwasser T; Institute for Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Wien, Austria.
  • Mashreghi MF; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • Wah Mak T; Institute of Infection Immunology, TWINCORE, Feodor-Lynen-Straße 7, 30625 Hannover, Germany.
  • Lohoff M; German Rheumatism Research Center Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Nat Commun ; 6: 8576, 2015 Oct 13.
Article en En | MEDLINE | ID: mdl-26815406
Regulatory T-cells induced via IL-2 and TGFß 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. TGFß 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 TGFß. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Linfocitos T Reguladores / Factores de Transcripción Forkhead / Proteína Tirosina Fosfatasa no Receptora Tipo 2 Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2015 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Linfocitos T Reguladores / Factores de Transcripción Forkhead / Proteína Tirosina Fosfatasa no Receptora Tipo 2 Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2015 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido