Natural killer (NK) cells are involved in immune responses against tumors and microbes. NK-cell activation is regulated by intrinsic and extrinsic mechanisms that ensure NK tolerance and efficacy. Here, we show that the cytoplasmic signaling molecules Dok1 and Dok2 are tyrosine phosphorylated upon NK-cell activation. Overexpression of Dok proteins in human NK cells reduces cell activation induced by NK-cell-activating receptors. Dok1 and Dok2 gene ablation in mice induces an NK-cell maturation defect and leads to increased IFN-γ production induced by activating receptors. Taken together, these results reveal that Dok1 and Dok2 proteins are involved in an intrinsic negative feedback loop downstream of NK-cell-activating receptors in mouse and human.
Dok1 and Dok2 proteins are expressed in NK cells and regulate NK-cell signaling
- Dok proteins are tyrosine phosphorylated upon engagement of NK-cell-activating receptors.
- Dok1 and Dok2 negatively regulate NK-cell activation induced by engagement of activating receptors.
- Combined deficiency in Dok1 and Dok2 impairs NK-cell development in vivo.