Lkb1维持Treg细胞稳定性对正常与GVHD情况下造血干细胞自稳的调控作用

The normal hematopoietic function of HSCs depends on the balance between HSC activation and quiescence states maintained by multiple supportive cells in the hematopoiesis niche. Foxp3+ Regulatory T (Treg) cells are a specialized lineage of T cells characterized by their immune suppressor function, and they are located close to HSCs, and play an important role in keeping the immune privilege of HSCs, but whether Tregs affect HSC self-renewal and differentiation is unknonwn. We have previously proved that Lkb1 is a critical maintainer of Treg lineage stability, and loss of Lkb1 in Treg cells led to decreased number of BM Treg cells, and impaired HSC self-renewal and differentiation function. In human graft versus host disease (GVHD) patients. BM Treg cells were diminished and Lkb1 expression levels in Treg cells were decreased, but the relationship between them, and how do they affect HSCs remain unclear, This project will integrate patient sample, transgenic mice and bone marrow transplantation models to study the role of Lkb1 in maintaining stability of Treg to regulate homeostasis and function of HSCs under normal and GVHD conditions, so as to extend the theory of micro-environmental control of HSC function, and to explore the relevant clinical values.

HSCs正常造血功能的维持依赖于造血龛（niche）内多种支持细胞对HSCs在静息与分化状态间平衡性的维持。调节性T细胞（Treg）是具有抑制功能的特殊T细胞亚群，已知Treg在niche紧邻HSCs，维持骨髓HSCs的免疫豁免特性，但其是否调控HSCs的更新和分化功能未被研究。我们前期研究发现Lkb1蛋白是Treg谱系稳定性的关键调控因子，骨髓Treg缺失Lkb1致Treg数量减少，HSCs自我更新和分化功能障碍，但相关分子机制未明。而移植物抗宿主病（GVHD）患者骨髓Treg数量减少，Treg中Lkb1表达下降，但这两者之间的因果关系，及其对HSCs的影响却不清楚。本研究将利用临床患者样本、转基因小鼠与骨髓移植模型等研究手段，探讨Lkb1在常态与GVHD条件下通过影响Treg稳定性对HSCs自稳和功能的调控作用及相关分子机制，以拓展微环境调控HSC自稳的理论体系，并探讨潜在临床价值。

Treg的数量减少和功能缺陷，被认为是导致骨髓移植后发生急性移植物抗宿主病（aGVHD）的重要的原因，但是既往研究均是在群体细胞的水平，不利于深度解析aGVHD中Treg的缺陷机制。我们以健康人和移植患者外周血以及骨髓来源的Treg为研究对象，首次运用单细胞转录组学及单细胞TCR技术从单细胞尺度系统性比较了人Treg在稳态和aGVHD状态下的异质性群体和分化路径。我们也探索了Lkb1对免疫细胞功能和代谢的调控作用。此外，基于实验室在T细胞基础研究方面的进展，以及完善的免疫研究平台，在免疫细胞治疗方面也相继开展了一些基础和转化研究。相关研究成果发表在Journal of Hematology & Oncology、Nature Communications、Frontiers in Immounology等期刊杂志上，为相关疾病临床治疗提供重要的理论基础。