KIR2DS4

KIR2DS4 is the only activating two-domain KIR carried by both KIR A and B haplotypes, making it the most prevalent activating KIR in human populations. KIR2DS4 is a type I transmembrane protein with D1-D2 Ig domains, a short tail, and DAP12 association via its charged transmembrane lysine, activating NK cells through SYK signaling. Uniquely among activating KIRs, KIR2DS4 has a defined HLA ligand: it recognizes a subset of HLA-C allotypes of both C1 and C2 groups (e.g., HLA-C*05, *08 and some others), plus weakly the broadly expressed HLA-A*11; however, a common deletion variant of the KIR2DS4 gene (KIR2DS4-del, present in most individuals) truncates the extracellular domain and eliminates ligand binding, so functional full-length KIR2DS4 is carried by only a minority of people. KIR2DS4 participates in antiviral NK responses, including control of hepatitis C and hantavirus infections, affects graft-versus-leukemia effects in transplantation, and full-length KIR2DS4 is enriched in certain autoimmune associations including ankylosing spondylitis.