KIR3DL3 is an inhibitory immune receptor that functions as a crucial checkpoint regulator in immune responses. The protein primarily functions as a coinhibitory receptor that binds to HHLA2 (HERV-H LTR-associating protein 2), a B7 family ligand, to suppress immune cell activation 1. KIR3DL3 is predominantly expressed on CD56dim NK cells and terminally differentiated effector memory CD8+ T cells (CD8+ TEMRA), with KIR3DL3+ CD8+ TEMRA cells acquiring an NK-like phenotype 1. The receptor also shows enriched expression in γδ and CD8+ T cells in tissue-resident populations, particularly in lungs and digestive tract 2. Mechanistically, KIR3DL3 recruitment to the immunological synapse upon HHLA2 engagement leads to coinhibition of CD8+ T and NK cell function through recruitment of phosphatases SHP-1 and SHP-2, which attenuate Vav1, ERK1/2, AKT, and NF-κB signaling pathways 1. In disease contexts, the KIR3DL3-HHLA2 pathway represents a significant immunosuppressive mechanism that tumors exploit for immune evasion 1. HHLA2+ tumors from kidney, lung, gallbladder, and stomach show infiltration by KIR3DL3+ immune cells, and KIR3DL3 blockade has demonstrated therapeutic efficacy in multiple humanized mouse tumor models 1. The receptor shows polymorphic expression with variants affecting promoter activity and protein levels, suggesting personalized therapeutic targeting potential 2.