KIR2DS1 is an activating killer cell immunoglobulin-like receptor expressed on natural killer (NK) cells that recognizes HLA-C group 2 (C2) molecules 1. Unlike its inhibitory counterpart KIR2DL1, KIR2DS1 contains a short cytoplasmic tail coupled to activating signaling through the DAP12 adaptor protein, enabling NK cell activation rather than inhibition 2. KIR2DS1 binding to HLA-C2 is peptide-dependent, with specific HLA-C peptide complexes required for optimal receptor engagement and NK cell activation 3. KIR2DS1 recognition is notably enhanced when HLA-C is modulated by human cytomegalovirus infection, suggesting a role in viral immunity 1. In allogeneic hematopoietic stem cell transplantation, KIR2DS1+ donor NK cells exhibit enhanced alloreactive killing of recipient leukemic cells, dendritic cells, and T cells, and can acquire CCR7 chemokine receptors to migrate toward lymph nodes, preventing graft-versus-host disease 24. Conversely, in antibody-dependent cellular cytotoxicity assays, KIR2DS1 expression suppresses NK cell degranulation, suggesting context-dependent functional outcomes 5. Additionally, KIR2DS1 binds malaria parasite RIFINs displayed on infected erythrocytes, activating NK cells to target infected cells 6. KIR2DS1 genetic variation shows limited association with atopic dermatitis compared to inhibitory KIR alleles 7.