Abstract：
The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring. Three months later, we measured the ex vivo cytokine responses against heterologous stimuli, analyzed gene expressions and epigenetic signatures of the immune cells, and compared these with the baseline before vaccination. BCG vaccination during winter induced a stronger increase in the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) upon stimulation with different bacterial and fungal stimuli, compared to BCG vaccination in spring. In contrast, winter BCG vaccination resulted in lower IFNγ release in PBMCs compared to spring BCG vaccination. Furthermore, NK cells of the winter-vaccinated people had a greater pro-inflammatory cytokine and IFNγ production capacity upon heterologous stimulation. BCG had only minor effects on the transcriptome of monocytes 3 months later. In contrast, we identified season-dependent epigenetic changes in monocytes and NK cells induced by vaccination, partly explaining the higher immune cell reactivity in the winter BCG vaccination group. These results suggest that BCG vaccination during winter is more prone to induce a robust trained immunity response by activating and reprogramming the immune cells, especially NK cells. (Dutch clinical trial registry no. NL58219.091.16).
摘要：
BacilleCalmette-Guerin（BCG）疫苗是先天免疫记忆（也称为训练免疫）的公认诱导剂，在异源二次刺激时导致细胞因子产生增加。已知固有免疫反应受季节影响，但是季节是否会影响受过训练的免疫力的诱导尚不清楚。探讨季节对卡介苗诱导的天然免疫记忆的影响,我们在冬季或春季为健康志愿者接种卡介苗。三个月后,我们测量了离体细胞因子对异源刺激的反应，分析了免疫细胞的基因表达和表观遗传特征，并将这些与疫苗接种前的基线进行比较。在不同的细菌和真菌刺激刺激下，冬季BCG疫苗可诱导外周血单核细胞（PBMC）产生的促炎细胞因子增加。与春季接种卡介苗相比。相比之下,与春季卡介苗接种相比，冬季卡介苗接种导致PBMC中IFNγ释放较低。此外，在异源刺激下，冬季接种疫苗的人的NK细胞具有更大的促炎细胞因子和IFNγ生产能力。3个月后，BCG对单核细胞的转录组仅有较小的影响。相比之下,我们确定了疫苗接种诱导的单核细胞和NK细胞的季节依赖性表观遗传变化，部分解释了冬季卡介苗接种组较高的免疫细胞反应性。这些结果表明，冬季接种卡介苗更容易通过激活和重新编程免疫细胞来诱导强大的训练免疫反应。特别是NK细胞。(荷兰临床试验登记号NL58219.091.16）。
