Carlomagno Simona, Falco Michela, Bono Maria, Alicata Claudia, Garbarino Lucia, Mazzocco Michela, Moretta Lorenzo, Moretta Alessandro, Sivori Simona
Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.
Istituto Giannina Gaslini, Genova, Italy.
Front Immunol. 2017 May 26;8:581. doi: 10.3389/fimmu.2017.00581. eCollection 2017.
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-B51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80 individuals, including those carrying particular KIR/HLA combination settings. In addition, killing of HLA-B51 transfected target cells mediated by KIR3DS1/NKG2A natural killer (NK) cell clones from Bw4-I80 donors could be partially inhibited by antibody-mediated masking of KIR3DS1. Interestingly, KIR3DS1-mediated recognition of HLA-B51 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 gene copy numbers, the positive signal generated by the engagement of KIR3DS1 by HLA-B51 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 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 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.
多项研究描述了杀伤细胞免疫球蛋白样受体（KIR）/HLA基因组合与多种疾病临床结局之间的关联。特别是，已描述了KIR3DS1和HLA-B Bw4-I80在控制病毒感染中的重要联合作用，以及在单倍体造血干细胞移植中配备激活型KIR的供体对白血病复发具有更高的保护作用。在此，我们表明KIR3DS1在识别靶细胞上的HLA-B51（Bw4-I80）表面分子时介导阳性信号，并且这种激活仅在Bw4-I80个体中发生，包括那些携带特定KIR/HLA组合的个体。此外，来自Bw4-I80供体的KIR3DS1/NKG2A自然杀伤（NK）细胞克隆介导的对HLA-B51转染靶细胞的杀伤作用可被抗体介导的KIR3DS1封闭部分抑制。有趣的是，在通过单克隆抗体介导的阻断降低NKG2D功能的实验条件下，KIR3DS1介导的对HLA-B51的识别能得到更好的体现。这种实验方法可能模拟了某些病毒感染中发生的NKG2D功能受损。我们还表明，在源自携带2个基因拷贝数的HLA-B Bw4-T80供体的KIR3DS1/NKG2A NK细胞克隆中，HLA-B51与KIR3DS1结合产生的阳性信号导致对HLA-B*51转染靶细胞的杀伤更有效。此外，在这些克隆中，检测到KIR3DS1与NKG2D表面密度之间存在直接相关性，而NKp46的表达与KIR3DS1的表达呈负相关。最后，我们分析了来自携带细胞质KIR3DL1的HLA-B Bw4供体的KIR3DS1/NKG2A NK细胞克隆。尽管这些克隆表面KIR3DS1的表达水平较低，但它们表现出与源自表达表面KIR3DL1的HLA-B Bw4供体的NK细胞克隆相当的反应。总之，这些数据表明，在特定的KIR/HLA组合中，KIR3DS1可能在人类NK细胞的教育过程中发挥作用。
