Whole Blood Profiling of Bacillus Calmette-Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation.
Whole Blood Profiling of Bacillus Calmette-Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation.
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DOI：
10.3389/fimmu.2017.00644
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发表时间：
2017
影响因子：
7.3
通讯作者：
Dockrell HM
中科院分区：
文献类型：
--
作者：
Smith SG;Kleinnijenhuis J;Netea MG;Dockrell HM
婴儿接种卡介苗（BCG）可激活免疫反应的先天臂和适应性臂。这些反应的抗细菌作用很可能是卡介苗能够预防儿童结核病的原因。也有证据表明，卡介苗接种对低出生体重婴儿与结核病无关的死亡率具有异源保护作用。当体外用不相关的微生物刺激重新刺激接种过bcg的成人细胞时，这种效应的一种可能的作用机制，即诱导经过训练的先天免疫，已得到证实。我们的目的是检查一个广泛的分泌免疫生物标志物小组，以表征婴儿训练先天免疫的概况。在卡介苗接种4个月后或未接种疫苗的对照婴儿进行48小时全血刺激。兴奋剂为脂多糖；Pam3Cys (P3C);热杀灭白色念珠菌、金黄色葡萄球菌、大肠杆菌和结核分枝杆菌的裂解物。42-plex头阵列检测培养上清中分泌的细胞因子和趋化因子，流式细胞术检测单核细胞和自然杀伤细胞（NK）活化标志物的表达。接种bcg的婴儿在不同的非特异性先天免疫刺激下表现出11种细胞因子和趋化因子的增加：表皮生长因子（EGF）；eotaxin;il - 6;IL-7;引发;il - 10;IL-12p40;单核细胞趋化蛋白-3；巨噬细胞炎性蛋白-1α；可溶性CD40配体和血小板衍生生长因子(PDGF)-AB/BB。尽管每种刺激物都能诱导不同的反应谱，但三种分析物EGF、IL-6和PDGF-AB/BB在Pam3Cys、白色假丝酵母菌和金黄色葡萄球菌刺激后通常更高。相反，某些细胞因子如干扰素γ诱导蛋白-10、IL-2、IL-13、IL-17、GM-CSF和GRO在接种bcg的婴儿中被抑制，而TNFα或IL-1β的产生未被检测到增加。我们没有观察到单核细胞表面激活标志物在非特异性刺激下的伴随的、与bcg相关的变化，但我们检测到NK细胞对Pam3Cys的反应中CD69的表达显著增加。pam3cys诱导的NK细胞活化与IL-12p40和IL-10对同一刺激物的反应大小相关。本研究揭示了一种新的细胞因子/趋化因子生物标志物的特征，即bcg诱导的婴儿先天免疫训练，以及NK细胞参与这些反应。
Vaccination of infants with bacillus Calmette–Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated in vitro with non-related microbial stimuli. Our aim was to examine an extensive panel of secreted immune biomarkers to characterize the profile of trained innate immunity in infants. Stimulation of whole blood for 48 h was performed 4 months after BCG vaccination, or in control unvaccinated infants. Stimulants were lipopolysaccharide; Pam3Cys (P3C); heat-killed Candida albicans, Staphylococcus aureus, Escherichia coli, and a lysate of Mycobacterium tuberculosis. Culture supernatants were tested for secreted cytokines and chemokines by 42-plex bead array and monocytes and natural killer (NK) cells assessed for expression of activation markers by flow cytometry. BCG-vaccinated infants displayed increases in 11 cytokines and chemokines in response to different non-specific innate immunity stimuli: epidermal growth factor (EGF); eotaxin; IL-6; IL-7; IL-8; IL-10; IL-12p40; monocyte chemotactic protein-3; macrophage inflammatory protein-1α; soluble CD40 ligand and platelet-derived growth factor (PDGF)-AB/BB. Although each stimulant induced a distinct response profile, three analytes, EGF, IL-6, and PDGF-AB/BB, were commonly higher after stimulation with Pam3Cys, C. albicans, and S. aureus. Conversely, certain cytokines such as interferon gamma-inducible protein-10, IL-2, IL-13, IL-17, GM-CSF, and GRO were suppressed in BCG-vaccinated infants, while no increases in TNFα or IL-1β production were detected. We did not observe a concomitant, BCG-associated change in monocyte surface activation markers in response to non-specific stimuli, but we detected a significant increase in CD69 expression on NK cells in response to Pam3Cys. Pam3Cys-induced NK cell activation correlated with the magnitude of IL-12p40 and IL-10 responses to the same stimulant. This study reveals a novel cytokine/chemokine biomarker signature of BCG-induced trained innate immunity in infants and the involvement of NK cells in these responses.