KIR2DS4 is an activating natural killer (NK) cell receptor that recognizes HLA-C alleles and plays important roles in innate immunity and transplantation outcomes. The gene exhibits significant polymorphism, with a common deletion variant (KIR1D) that produces a truncated, soluble protein lacking transmembrane and cytoplasmic domains 1. This deletion variant occurs at high frequencies in many populations, with significant regional variation observed 2. KIR2DS4 demonstrates specific ligand recognition, showing strong preference for peptides with tryptophan at position 8 presented by HLA-C*05:01, particularly bacterial RecA epitopes from pathogens including Helicobacter, Chlamydia, and Brucella 3. The receptor's clinical significance is evident in hematopoietic stem cell transplantation, where donor KIR2DS4 variants influence acute graft-versus-host disease risk, cytomegalovirus reactivation, and overall survival 45. Additionally, KIR2DS4 combinations with specific HLA alleles affect HIV disease progression 6 and correlate with EBV antibody titers, suggesting distinct responses to different viral infections 7. The receptor's evolutionary importance is supported by inverse worldwide frequency distributions with its HLA-C*05:01 ligand, indicating balancing selection 3.