KIR₃DS₁-mediated recognition of HLA-*B₅₁: Modulation of KIR3DS1 responsiveness by self HLA-B allotypes and effect on NK cell licensing

Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR₃DS₁ and HLA-B Bw₄-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR₃DS₁ mediates positive signals upon recognition of HLA-B*₅₁ (Bw₄-I80) surface molecules on target cells and that this activation occurs only in Bw₄-I80^neg individuals, including those carrying particular KIR/HLA combination settings. In addition, killing of HLA-B*₅₁ transfected target cells mediated by KIR₃DS₁⁺/NKG2A⁺ natural killer (NK) cell clones from Bw₄-I80^neg donors could be partially inhibited by antibody-mediated masking of KIR₃DS₁. Interestingly, KIR₃DS₁-mediated recognition of HLA-B*51 could be better appreciated under experimental conditions in which the function of NKG2D was reduced by mAb-mediated blocking. This experimental approach may mimic the compromised function of NKG2D occurring in certain viral infections. We also show that, in KIR₃DS₁+/NKG₂A⁺ NK cell clones derived from an HLA-B Bw₄-T80 donor carrying 2 KIR₃DS1 gene copy numbers, the positive signal generated by the engagement of KIR₃DS₁ by HLA-B*₅₁ resulted in a more efficient killing of HLA-B*51-transfected target cells. Moreover, in these clones, a direct correlation between KIR₃DS₁ and NKG₂D surface density was detected, while the expression of NKp₄₆ was inversely correlated with that of KIR₃DS₁. Finally, we analyzed KIR₃DS₁⁺/NKG₂A⁺ NK cell clones from a HLA-B Bw4^neg donor carrying cytoplasmic KIR₃DL₁. Although these clones expressed lower levels of surface KIR3DS1, they displayed responses comparable to those of NK cell clones derived from HLA-B Bw₄^neg donors that expressed surface KIR₃DL₁. Altogether these data suggest that, in particular KIR/HLA combinations, KIR₃DS₁ may play a role in the process of human NK cell education.