Constitutive activation of MEK1 promotes Treg cell instability in vivo [Immunology]

October 31st, 2014 by Guo, J., Zhang, J., Zhang, X., Zhang, Z., Wei, X., Zhou, X.

The instability of regulatory T (Treg) cells is involved in the pathogenesis of autoimmune diseases and also highlights safety concerns with regard to clinical Treg cell therapy. Cell-intrinsic molecular events linked to this Treg cell instability in vivo are still obscure. Here, we developed a novel luciferase-based reporter system and performed an unbiased screening for kinases that potentially modulate Foxp3 function. We found that the active form of COT/Tpl2 specifically inhibits the DNA binding activity of Foxp3 through a MEK-ERK-dependent pathway. Moreover, Treg-specific expression of activated MEK1 led to dysregulation of Treg function and instability of Foxp3 expression in vivo. Our results support the hypothesis that outside inflammatory signals act through the Cot/Tpl2-MEK-ERK signaling pathway to destabilize the Treg lineage.