Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination’s profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.

虽然 Bacille-Calmette-Guérin （BCG） 疫苗用于预防结核病，但它也可以预防各种非分枝杆菌感染。然而，人类的潜在保护机制尚不完全清楚。在这里，我们以单细胞分辨率调查了在 BCG 疫苗接种或安慰剂之前和之后 90 天抽吸的人骨髓的基因表达和染色质景观。我们发现 BCG 改变了人类造血干细胞和祖细胞 （HSPCs） 的基因表达和表观遗传谱。基因表达的变化主要发生在未定型的干细胞中。相比之下，染色质可及性的变化在受 Kruppel 样因子 （KLF） 和早期生长反应 （EGR） 转录因子影响的分化祖细胞中最为普遍，并且与配对外周血单核细胞 （PBMC） 的白细胞介素 （IL）-1β 分泌能力高度相关 （r > 0.8）。我们的研究结果阐明了 BCG 疫苗接种对 HSPC 的深远而持久的影响及其对先天免疫反应和训练免疫力的影响。