Plasmactoid dendritic cells express EphA2 to negatively regulate type I interferon production in response to viral infection

Abstract

Abstract Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN-I) in response to viral infection. But how such responses are negatively regulated remains poorly defined. Here, we report that the EPH receptor 2 (EphA2), a member of the protein-tyrosine kinase subfamily of ephrin receptors, is selectively expressed in pDCs. Knockout of EphA2 enhanced IFN-I production in pDCs from infection with influenza virus or DNA virus of HSV-1. The expression of Epha2 was dramatically down-regulated after pDCs activation. Surprisingly, challenge of EphA2−/− mice with HSV-I resulted in lethal inflammation and tissues including stomach, intestine, lung and liver damage due to massive production of IFN-I, while depletion of pDCs, partially blocking of IFN-I receptor (IFNAR) signaling, or transplantation of wild type bone marrow cells into irradiated EphA2−/− mice protected mice from this lethal infection. Mechanistically, EphA2 phosphorylates tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), a key adaptor protein in pDCs function, and inhibits IRF7 activation to reduce IFN-I production in pDCs. These data demonstrate that pDCs expressed EphA2 limits excessive IFN-I production in response to viral infection to avoid uncontrolled inflammation and multiple organ failure. And this finding may provide attractive opportunities for therapeutic targeting pDCs mediated acute inflammation.