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

作者：Bothur Evita; Raifer Hartmann; Haftmann Claudia; Stittrich Anna Barbara; Bruestle Anne; Brenner Dirk; Bollig Nadine; Bieringer Maria; Kang Chol Ho; Reinhard Katharina; Camara Baerbel; Huber Magdalena; Visekruna Alexander; Steinhoff Ulrich; Repenning Antje; Bauer Uta Maria; Sexl Veronika; Radbruch Andreas; Sparwasser Tim; Mashreghi Mir Farzin; Mak Tak Wah; Lohoff Michael^*

来源：Nature Communications, 2015, 6(1): 8576.

DOI：10.1038/ncomms9576

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

• 出版日期2015-10
• 单位河北医科大学