KIR2DS5 is an activating natural killer (NK) cell receptor that recognizes C2 epitopes of HLA-C alleles 1. This receptor bridges innate and adaptive immunity by stimulating NK cell cytotoxicity and cytokine production, including interferon-gamma 1. However, receptor function varies substantially across populations due to allelic diversity; European populations predominantly carry the non-functional KIR2DS5*002 variant, while African populations harbor multiple functional C2-specific allotypes with approximately 20-40% of the ligand-binding avidity of inhibitory KIR2DL1 and activating KIR2DS1 1. KIR2DS5 is present in ~26-33% of individuals globally and is restricted to KIR 'B' haplotypes 23. Clinically, KIR2DS5 presence demonstrates protective associations with ankylosing spondylitis (OR=0.47), endometriosis (OR=0.25), and acute kidney graft rejection (OR=0.44) 4. In pregnancy, reduced KIR2DS5 expression in decidual NK cells correlates with preeclampsia risk, potentially through impaired GM-CSF production via JAK2/STAT5 signaling 5. Conversely, KIR2DS5 overrepresentation associated with increased alcoholic cirrhosis susceptibility in patients over 54 years 6. These divergent disease associations reflect the complex interplay between KIR2DS5 allelic variants, HLA-C ligand availability, and population-specific immunological contexts.