FcRγ-dependent NK cell licensing through CD244 promotes antitumour immunity

Natural killer (NK) cell licensing is an educational process that enhances responsiveness to activating signals in maturing NK cells and is predominantly regulated by major histocompatibility complex (MHC) class I-specific inhibitory signals. However, the role of non-MHC signalling in this process remains unclear. Here, we investigated the role of FcRγ, an adaptor protein associated with activating receptors, in the regulation of NK cell responsiveness. We showed that while FcRγ does not affect NK cell development, maturation, or cytotoxic molecule expression, FcRγ-deficient (Fcer1g-/-) NK cells exhibit hyporesponsiveness to tumour cells and impaired tumour control in vivo. Transcriptional and proteomic analyses revealed significantly reduced expression of the CD244 receptor in Fcer1g-/- NK cells, which contributed to their functional maturation and licensing, suggesting an additional, non-redundant pathway of NK cell education. Pre-treatment with common gamma-chain (γc) cytokines (IL-2 or IL-15) rescued Fcer1g-/- NK cells from hyporesponsiveness and restored their antitumour activity. These findings demonstrate that FcRγ plays a crucial role in licensing NK cells for antitumour immune responses through CD244 signalling, and that γc cytokines can override the absence of this signalling.