FcRγ-Dependent NK Cell Licensing through CD244 Promotes Antitumor Immunity

Abstract NK cell licensing is an educational process that enhances responsiveness to activating signals in maturing NK cells and is predominantly regulated by MHC class I–specific inhibitory signals. However, the role of non-MHC signaling in this process remains unclear. In this study, we investigated the role of FcRγ, an adaptor protein associated with activating receptors, in the regulation of NK cell responsiveness. We showed that although FcRγ does not affect NK cell development, maturation, or cytotoxic molecule expression, FcRγ-deficient (Fcer1g−/−) NK cells exhibit hyporesponsiveness to tumor cells and impaired tumor control in vivo. Transcriptional and proteomic analyses revealed significantly reduced expression of CD244 in Fcer1g−/− NK cells, which contributed to their functional maturation and licensing, suggesting an additional, nonredundant pathway of NK cell education. Pretreatment with common γ-chain cytokines (IL2 or IL15) rescued Fcer1g−/− NK cells from hyporesponsiveness and restored their antitumor activity. These findings demonstrate that FcRγ plays a crucial role in licensing NK cells for antitumor immune responses through CD244 signaling and that γ-chain cytokines can override the absence of this signaling.