| Title: |
Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1 |
| Authors: |
Bothur, E.; Raifer, H.; Haftmann, C.; Stittrich, A. B.; Brustle, A.; Brenner, D.; Bollig, N.; Bieringer, M.; Kang, C. H.; Reinhard, K.; Camara, B.; Huber, M.; Visekruna, A.; Steinhoff, U.; Repenning, A.; Bauer, U. M.; Sexl, V.; Radbruch, A.; Sparwasser, T.; Mashreghi, M. F.; Mak, T. W.; Lohoff, M. |
| Source: |
Bothur, E, Raifer, H, Haftmann, C, Stittrich, A B, Brustle, A, Brenner, D, Bollig, N, Bieringer, M, Kang, C H, Reinhard, K, Camara, B, Huber, M, Visekruna, A, Steinhoff, U, Repenning, A, Bauer, U M, Sexl, V, Radbruch, A, Sparwasser, T, Mashreghi, M F, Mak, T W & Lohoff, M 2015, 'Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1', Nature Communications, vol. 6, 8576. https://doi.org/10.1038/ncomms9576 |
| Publication Year: |
2015 |
| Collection: |
University of Southern Denmark: Research Output / Syddansk Universitet |
| Subject Terms: |
Animals; Blotting; Western; CD4-Positive T-Lymphocytes/metabolism; Cells; Cultured; Female; Flow Cytometry; Forkhead Box Protein O1; Forkhead Transcription Factors/genetics; Male; Mice; Protein Tyrosine Phosphatase; Non-Receptor Type 2/genetics; Receptors; Antigen; T-Cell/genetics; T-Lymphocytes; Regulatory/metabolism |
| Description: |
Regulatory T-cells induced via IL-2 and TGF 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. TGF 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 TGF. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/26815406; info:eu-repo/semantics/altIdentifier/wos/000364932600023; info:eu-repo/semantics/altIdentifier/pissn/2041-1723; info:eu-repo/semantics/altIdentifier/eissn/2041-1723 |
| DOI: |
10.1038/ncomms9576 |
| Availability: |
https://portal.findresearcher.sdu.dk/da/publications/ae0fa504-460b-4cb8-bf5e-cf8259ece534; https://doi.org/10.1038/ncomms9576 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.DD58EDFC |
| Database: |
BASE |