KIR2DL3 is an inhibitory receptor on natural killer (NK) cells that recognizes HLA-C group 1 alleles (C1 epitopes), preventing NK cell activation and cytolysis of target cells 1. The receptor functions through inhibitory signaling pathways that regulate NK cell licensing, with licensing capacity similar to KIR2DL1 despite weaker binding affinity to HLA-C 2. Structural studies reveal that KIR2DL3 exhibits distinct docking geometries when binding HLA-C compared to its closely related counterpart KIR2DL2, contributing to functional differences in HLA-C1 allotype recognition 3. The receptor shows evolutionary adaptation, with weaker KIR2DL3 variants selected in populations with high-frequency HLA-C*07 to maintain balanced NK cell education 4. Clinically, KIR2DL3 expression is associated with multiple diseases. Higher KIR2DL3 levels correlate with increased psoriatic arthritis risk 5 and stage 4 neuroblastoma compared to early-stage disease 6. Conversely, KIR2DL3 is downregulated in CD8+ T cells from lupus patients with end-stage renal disease 7. These associations suggest KIR2DL3 plays important roles beyond NK cell regulation, potentially serving as a biomarker for disease severity and therapeutic targeting in various immune-mediated conditions.