肝脏特有NKT细胞亚群的发现与深入验证

As a lymphoid organ, liver contains abundant of innate / innatelike immune cells and predominantly induces immune tolerance, which maintains homeostasis and physiological function of liver. However, the mechanisms are still not clear, due to the limited knowledge on liver resident innate / innatelike immune cells. As one of the most important resident cells in liver, NKT cell is 10 to 20 fold more enriched in liver than in other tissues. Identifying and characterising the liver specific subset of NKT cell will help us to understand the regional immunity of liver and the mechanisms in regulating immune homeostasis. Recent studies on metabolic diseases critically linked NKT cell to meta-inflammation. Discovering the role of liver specific NKT subset in maintaining immune homeostasis and inhibiting meta-inflammation would shed light on a new direction to prevent the onset of diseases. For three years, we are working on a liver specific new NKT cell subset, which is CD24+ LinHigh, 2% - 5% among liver NKT cells, and predominantly produces IL13. In the future, we will try to demonstrate the origin, development, lineage determining transcription factors, and function of this liver specific NKT cell subset, and further explore the connection between this new subset and metabolic diseases with animal models.

肝脏免疫稳态是维持肝脏正常生理功能的保障,包括富含天然免疫细胞和免疫耐受二大特性，二者内在联系由于肝脏天然免疫细胞基本属性不清而至今未能解读。肝脏NKT细胞含量是其它脏器的10-20倍，是否含有新的特有亚群以及阐明其发育分化路径与功能特性对于解读肝脏免疫稳态以及区域免疫特性有重要意义。近来发现NKT细胞与组织免疫稳态失衡以及代谢炎症的发生密切相关，验证肝脏特有NKT细胞是否通过其免疫负调功能维持肝脏免疫稳态,并阻止肝脏代谢性炎症的发生发展具有重要意义。我们通过三年的研究，发现了一群肝脏特有的NKT细胞亚群（CD24+ LinHigh），占肝脏NKT细胞的2% - 5%，主要分泌IL-13；拟进一步阐明这群NKT细胞的来源及发育分化途径、谱系稳态的转录调控、负调功能等基本属性，同时通过肝脏代谢性炎症相关的疾病模型，深入揭示这群肝脏特有NKT细胞与肝脏免疫稳态维持以及疾病发生发展的关系。

NKT细胞是固有样T淋巴细胞的典型代表，具有组织驻留的特性，大量富集在肝脏。已有研究表明NKT细胞与肝脏免疫以及肝脏疾病的发生都密切相关，但NKT细胞在维持肝脏特殊免疫属性中的作用机制以及在肝脏疾病发生发展中的作用机制仍不清楚。本项目发现了肝脏特有的 NKT细胞亚群以及记忆性NKTFH亚群，揭示了这些新亚群与肝脏免疫、体液免疫的关系。此外，我们还揭示了肝肠对话及组织微环境中细胞间的对话、代谢分子对NKT细胞功能及肝脏疾病的调控机制。我们的研究结果不仅阐释了NKT细胞在调控体液免疫和维持组织免疫稳态以及调控疾病发生发展中的作用机制，也为新的疫苗设计和肿瘤免疫治疗提供了理论基础和前期数据。