Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1.

  • Experimental and¬†Molecular Immunology
October 13, 2015 By:
  • Bothur E
  • Raifer H
  • Haftmann C
  • Stittrich AB
  • Brustle A
  • Brenner D
  • Bollig N
  • Bieringer M
  • Kang CH
  • Reinhard K
  • Camara B
  • Huber M
  • Visekruna A
  • Steinhoff U
  • Repenning A
  • Bauer UM
  • Sexl V
  • Radbruch A
  • Sparwasser T
  • Mashreghi MF
  • Wah Mak T
  • Lohoff M.

Regulatory T-cells induced via IL-2 and TGFbeta 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. TGFbeta 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 TGFbeta. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.

2015 Oct. Nat Commun.6:8576.
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