TY - JOUR
T1 - Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1
AU - Bothur, Evita
AU - Raifer, Hartmann
AU - Haftmann, Claudia
AU - Stittrich, Anna Barbara
AU - Brustle, Anne
AU - Brenner, Dirk
AU - Bollig, Nadine
AU - Bieringer, Maria
AU - Kang, Chol Ho
AU - Reinhard, Katharina
AU - Camara, Barbel
AU - Huber, Magdalena
AU - Visekruna, Alexander
AU - Steinhoff, Ulrich
AU - Repenning, Antje
AU - Bauer, Uta Maria
AU - Sexl, Veronika
AU - Radbruch, Andreas
AU - Sparwasser, Tim
AU - Mashreghi, Mir Farzin
AU - Wah Mak, Tak
AU - Lohoff, Michael
N1 - Funding Information:
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).
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/10/13
Y1 - 2015/10/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944144932&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/26815406
U2 - 10.1038/ncomms9576
DO - 10.1038/ncomms9576
M3 - Article
C2 - 26815406
AN - SCOPUS:84944144932
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 8576
ER -