NK cells and interferons

• Type I IFNs promote NK cell activation directly and also indirectly through IL-15 cis and trans presentation.
• NK cell early exposure to type I IFNs during antiviral immune response results in a preferential phosphorylation of STAT4 over STAT1, leading to IFN-γ production.
• NK cells chronic exposure to type I IFNs promotes a STAT1 preferential activation leading to an increase of NK cell cytotoxicity.
• NK cells can promote viral clearance and tissue protection by T cells or be the cause of virus persistence provoking chronic T cell activation and tissue damage.

The role of Natural Killer cells in host defense against infections as well as in tumour surveillance has been widely appreciated for a number of years. Upon recognition of “altered” cells, NK cells release the content of cytolytic granules, leading to the death of target cells. Moreover, NK cells are powerful producers of chemokines and cytokines, particularly Interferon-γ (IFN-γ), of which they are the earliest source upon a variety of infections. Despite being armed to fight against pathogens, NK cells become fully functional upon an initial phase of activation that requires the action of several cytokines, including type I IFNs. Type I IFNs are now recognized as key players in antiviral defense and immune regulation, and evidences from both mouse models of disease and in vitro studies support the existence of an alliance between type I IFNs and NK cells to ensure effective protection against viral infections.This review will focus on the role of type I IFNs in regulating NK cell functions to elicit antiviral response and on NK cell-produced IFN-γ beneficial and pathological effects.