Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells
Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells
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DOI：
10.3389/fimmu.2019.02741
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发表时间：
2019-11-27
影响因子：
7.3
通讯作者：
Ferrari, Guido
中科院分区：
文献类型：
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作者：
Fisher, Leigh;Zinter, Melissa;Ferrari, Guido
RV144 HIV-1 疫苗试验中感染风险相关性的二次分析表明，在观察到的保护作用中存在疫苗诱导的抗体依赖性细胞毒性 (ADCC) 反应，强调了在正在进行和未来的 HIV-1 疫苗试验中评估此类反应的重要性。然而，检测 HIV-1 感染者血清阳性个体血浆中 ADCC 活性的体外测定并不总是有效检测 HIV-1 疫苗接受者血浆中 ADCC 活性。在体内，ADCC介导的抗体必须在感染部位发挥作用，效应细胞在感染部位被趋化因子和细胞因子的局部环境招募和激活。基于之前的研究结果，即急性 HIV-1 感染期间白介素 15 (IL-15) 分泌增加并增强 NK 细胞介导的细胞毒性，我们假设 IL-15 预处理 NK 效应细胞可用于改善疫苗诱导的能够介导 ADCC 的抗体对感染细胞的杀伤。使用 HIV-1 感染性分子克隆 (IMC) 感染的靶细胞检测以及 HIV-1 疫苗接种者的血浆样本，我们发现效应细胞的 IL-15 处理提高了疫苗诱导抗体招募 ADCC 效应细胞的能力。通过免疫表型实验，我们发现这种杀伤力的提高可能是由于 IL-15 介导的 NK 效应细胞激活以及 IL-15 预处理的 NK 细胞中穿孔素和颗粒酶 B 的细胞内水平较高所致。我们还发现，使用 4 倍稀释系列的血浆并减去疫苗接种前的反应，导致安慰剂接受者中的反应率最低，并且治疗组之间存在显着的分离。这是利用 IL-15 处理的效应细胞和优化的分析方法来改善 HIV-1 疫苗诱导的 ADCC 反应检测的首次尝试，并将为未来 HIV 疫苗临床试验的分析提供信息。
The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, in vitro assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine recipients. In vivo, ADCC-mediating antibodies must operate at the site of infection, where effector cells are recruited and activated by a local milieu of chemokines and cytokines. Based on previous findings that interleukin 15 (IL-15) secretion increases during acute HIV-1 infection and enhances NK cell-mediated cytotoxicity, we hypothesized that IL-15 pretreatment of NK effector cells could be used to improve killing of infected cells by vaccine-induced antibodies capable of mediating ADCC. Using the HIV-1 infectious molecular clone (IMC)-infected target cell assay along with plasma samples from HIV-1 vaccine recipients, we found that IL-15 treatment of effector cells improved the ability of the vaccine-induced antibodies to recruit effector cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of NK effector cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated NK cells. We also found that using a 4-fold dilution series of plasma and subtraction of pre-vaccination responses resulted in lowest response rates among placebo recipients and significant separation between treatment groups. This represents the first attempt to utilize IL-15-treated effector cells and optimized analytical approaches to improve the detection of HIV-1 vaccine-induced ADCC responses and will inform analyses of future HIV vaccine clinical trials.