Abstract
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.
Highlights
Natural killer (NK) cells are lymphocytes of innate immunity that are involved in the host immune defenses against viruses and tumor cells
An important combined role played by KIR3DS1 and HLA-B Bw4I80 in controlling HIV infection [11, 12] and the recognition of specific HIV-derived peptides associated with HLA-B*57 alleles by KIR3DS1 have been described [15]
We provided the first evidence of a direct involvement of KIR3DS1 in the natural killer (NK)-mediated recognition of HLA-B*51 surface molecules expressed on target cells
Summary
Natural killer (NK) cells are lymphocytes of innate immunity that are involved in the host immune defenses against viruses and tumor cells. NK cells can exert cytotoxicity against transformed cells and release soluble factors important for regulating innate and adaptive immune responses [1, 2]. The NK cell function is controlled by an array of activating and inhibitory receptors, including the family of killer-cell immunoglobulin-like receptors (KIRs) [3]. KIR3DL1/S1 is the KIR gene characterized by the highest degree of polymorphism, and it is the only one including alleles coding for either inhibitory (KIR3DL1) or activating (KIR3DS1) receptors. KIR3DL1 is highly polymorphic, whereas KIR3DS1*013 is the most represented in all examined populations [7]. Despite the high degree of homology between these two KIR3D receptors, knowledge about KIR3DS1 function and ligand specificity is not completely defined so far
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