KIR3DL1 is a polymorphic inhibitory receptor expressed on natural killer (NK) cells and T cell subsets that recognizes HLA class I allotypes expressing the Bw4 epitope 1. The receptor functions to suppress NK cell cytotoxicity through binding to HLA-A and HLA-B molecules containing the Bw4 motif (residues 77-83), though additional HLA polymorphisms outside this core epitope modulate binding affinity in a nonadditive manner 2. KIR3DL1 exhibits exceptional functional diversity: sequence variants affect both cell-surface expression frequency and intensity, while a common allelic variant (KIR3DS1) encodes an activating receptor instead 1. Evolutionary analysis reveals KIR3DL1 as an archaic allele lineage preserved in Oceanian populations, with specific polymorphisms like phenylalanine 166 enhancing HLA binding specificity 3. Clinically, KIR3DL1 polymorphisms influence disease outcomes: KIR3DL1-negative NK and CD8 T cells associate with superior HIV-1 control in Bw4-homozygous individuals 4, while therapeutic KIR3DL1 blockade (via DX9 antibody) restores NK cell cytotoxicity against interferon-gamma-induced tumor resistance in melanoma 5. The receptor exemplifies how variable NK cell receptors diversify population-level immunity through coevolution with polymorphic ligands.