NK subsets display defined levels of enhanced response to “missing-self” that are determined by the combination of KIR and HLA polymorphisms in the donor. (A) NK subsets defined by single inhibitory MHC class I receptors respond differently to 721.221 target cells. For this donor (HLA-C1, Bw4; KIR A1A1), the NK subsets bearing only LILRB1, KIR2DL1, or 3DL2 gave weak responses, such as the receptor-null subset, whereas NK cells bearing NKG2A, KIR2DL3, or 3DL1 gave strong responses. (B) NK subsets, from the same donor, expressing different combinations of KIR3DL1, 2DL3, 2DL1, and NKG2A were analyzed for their cytokine and cytotoxic response to 221 cells. The vertical line gives the response level of the receptor-null subset. (C) How different combinations of HLA class I ligands and NK-cell receptors enhance the missing-self response of NK subsets to 221 cells. In all 58 donors, the enhanced response of NKG2A single-positive cells was constant (dotted vertical line), whereas the effects on KIR single-positive cells varied with donor HLA and KIR genotype. NKG2A, n = 58; 2DL1/S1⁺ C2⁻, n = 42; C2⁺2DL1*004⁺, n = 4; C2⁺2DL1*004⁻, n = 11; 2DL3⁺ Cw*7⁺, n = 16; Cw*7⁻Cw*12⁺, n = 7; Cw*7⁻Cw*12⁻B*46⁺, n = 4; Cw*7⁻Cw*12⁻ Cw*1402⁺, n = 4; Cw*01/03/08/1403⁺, n = 10; 2DL2/3⁺ C2/2, n = 5; 3DL1*001/002/15/20⁺ B*51/52⁺, n = 13; B4403⁺, n = 5; B*13⁺, n = 2; 3DL1⁺Bw4⁻ A*24⁺, n = 13; A*24⁻, n = 9; 3DL1*1502⁺, n = 22; 3DL1*007⁺, n = 5; 3DL1*005⁺, n = 8; 3DS1⁺, n = 1. *P < .05, ** P < .005, *** P < .001. Comparison of the effect by C1 was significant by ANOVA. P < .05 was considered statistically significant.