Decoding immunocompetence code that can reactivate aged hematopoietic stem cells

最近的研究表明，不仅是适应性免疫，而且先天免疫也能够记忆以前遇到的病原体，以发展训练免疫。越来越多的证据表明，造血干细胞在微生物感染后可以产生免疫记忆，但其具体机制尚不清楚。我们先前已经发现，在肠道炎症时，拟杆菌属物种（肠道中的革兰氏阴性细菌之一）渗透到体内并激活BM造血，其中造血祖细胞（HPC）被引导至肠道相关淋巴结并产生用于组织修复的抗炎骨髓细胞（Hayashi et al.，bioRxiv 2021）。因此，我们假设拟杆菌可能能够在造血干细胞及其衍生的先天免疫细胞上表观遗传地印记先天免疫记忆，发挥更强的免疫能力。为了验证我们的假设，我们首先用拟杆菌攻击小鼠，并进行体内脓毒症模型作为第二次攻击。微生物预刺激可以提供交叉保护作用，提高宿主的存活率。为了阐明潜在的机制，我们建立了一个新的生物信息学管道来整合单细胞测序数据，并在刺激后1个月确定了抗炎，先天免疫和代谢相关基因的表观遗传启动。拟杆菌还诱导致敏的HSC中活性组蛋白修饰的实质性变化。我们的数据表明，理解造血干细胞先天免疫记忆的形成、维持和消除可能有助于增强老年血液免疫系统的免疫能力。

Recent works show that not only adaptive immunity but also innate immunity is capable of memorizing previously-encountered pathogens to develop trained immunity. Accumulating evidences show that HSCs can develop immune memory after microbial infection, although the underlying mechanism still remains unclear. We have previously found that upon gut inflammation, Bacteroides species, one of gram negative bacteria in the gut, infiltrate into body and activate BM haematopoiesis in which hematopoietic progenitor (HPCs) are directed to gut-associated lymph node and generate anti-inflammatory myeloid cells for tissue repair (Hayashi et al., bioRxiv 2021). Thus, we hypothesize that Bacteroides might be able to epigenetically imprint an innate immune memory on HSCs and their derived innate immune cells that exert stronger immunocompetence. To test our hypothesis, we primarily challenged mice with Bacteroides and performed in vivo sepsis model as secondary challenge. Microbial prestimulation can provide cross-protective effect to improve host survival. To elucidate the underlying mechanism, we establish a novel bioinformatic pipeline to integrate single-cell sequencing data, and identified epigenetic priming in anti-inflammatory, innate immunity- and metabolism-related genes at 1-month post-stimulation. The Bacteroides also induced substantial changes in active histone modification in the primed HSCs. Our data suggest that understanding of formation, maintenance and abrogation of innate immune memory in HSCs might help to enforce immune-competent of aged hemato-immune system.