Natural killer cell receptor network (NKR network)

The Natural killer cell receptor network is a complex system of activating and inhibitory receptors that regulate the activity of natural killer (NK) cells and maintain self-tolerance (Long et al., 2013, Annu Rev Immunol). Inhibitory receptors, such as Killer-cell Immunoglobulin-like Receptors (KIRs) and NKG2A, recognize Major Histocompatibility Complex (MHC) class I molecules to prevent the destruction of healthy cells (Vivier et al., 2011, Science). Activating receptors, including NKG2D, CD16, and Natural Cytotoxicity Receptors (NCRs), trigger immune responses upon binding to ligands upregulated on stressed or malignant cells (Shifrin et al., 2014, Immunol Rev). In many cancers, the balance of this network is disrupted, favoring inhibitory signals that allow tumors to evade immune detection (Andre et al., 2018, Cell). Therapeutic strategies targeting this network include checkpoint inhibitors that block inhibitory receptors and multi-specific engagers that activate NK cells against specific tumor antigens (Sivori et al., 2019, J Exp Med). This network is also critical in the context of viral infections, where NK cells identify and eliminate infected cells that have downregulated MHC molecules (Jost and Altfeld, 2013, Annu Rev Immunol). Dysregulation of these receptors is implicated in autoimmune diseases and chronic inflammation, where NK cells may inappropriately attack host tissues (Poggi and Zocchi, 2014, Front Immunol). Overall, the NK-cell receptor network represents a major frontier in cancer immunotherapy, offering pathways distinct from T-cell-based approaches.

Other names

NK cell receptorsNKRsActivating and inhibitory NK cell receptorsNK cell checkpoint network

Modulation of the balance between activating and inhibitory signals to restore or enhance NK cell-mediated lysis of target cells (Sivori et al., 2019, J Exp Med).