Liver stroma enhances activation of TLR3-triggered NK cells through fibronectin

Recent studies demonstrate that tissue microenvironments may regulate development and functions of immune cells including dendritic cells, monocytes and T cells. However, there is no report about functional regulation of innate NK cells by tissue microenvironment. The liver is an organ abundant in NK cells and susceptible to virus infection. The number and cytotoxicity of liver NK cells have been shown to be increased during pathogenesis of viral hepatitis and contribute to liver damage. So, whether and how liver stromal microenvironment regulates NK cells need to be fully investigated. By preparing liver fibroblast stromal cells to mimic stromal microenvironment in liver, in this study we demonstrate that liver stroma could chemoattract and adhere TLR3-triggered NK cells, and further augment the cytotoxicity and IFN-gamma production of TLR3-triggered NK cells via fibronectin. Furthermore, the autocrined IFN-gamma from NK cells is required for the enhancement of TLR3-triggered NK cell activation by liver stroma. Our results suggest that liver stroma can recruit NK cells and promote activation of NK cells during viral infection, thus providing a mechanistic explanation for the increased number and cytotoxicity of liver NK cells which may cause liver damage during pathogenesis of viral hepatitis.