PDF(Pubmed)
Abstract：
There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed-direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer-Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16-known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.
摘要：
存在两种已知的自然杀伤(NK)细胞识别和杀死患病靶标的机制:(i)直接杀伤和(ii)抗体依赖性细胞介导的细胞毒性(ADCC)。我们研究了用于增强人类NK细胞杀伤功能的间接NK细胞活化策略。我们通过利用人类外周血单核细胞（PBMC）池内的toll样受体9（TLR9）激动作用导致导致NK细胞活化的强大干扰素信号级联这一事实来做到这一点。TLR9激动剂刺激后，富集NK细胞并将其掺入测定中以评估其杀死肿瘤细胞系靶标的能力。值得注意的是,观察到TLR9激动作用的不同影响-直接杀伤作用增强,而ADCC没有增加.为了确保观察到的差异效应不归因于人类捐赠者之间的差异，我们使用我们的自然杀伤-同时ADCC和直接杀伤试验（NK-SADKA）控制人与人之间的差异来概括观察结果。接下来,我们观察到治疗诱导的NK细胞表面CD16减少-已知由NK细胞活化后脱落。鉴于CD16在ADCC中的重要作用，这种脱落可以解释所观察到的TLR9激动作用对NK细胞介导的杀伤能力的不同影响。
