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-I80neg 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-I80neg 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
Bw4neg 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 Bw4neg 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
