NKT细胞分化成熟的调控机制

NKT细胞在胸腺中分化成熟，在外周组织系统中参与免疫应答和免疫相关疾病的调控。目前对于NKT细胞的来源、分化过程和免疫功能已经比较清楚，但是对于NKT细胞的免疫功能和作用特性如何在不同的分化阶段建立，分化与功能成熟的协同调控机制以及在生理和病理情况下NKT细胞功能作用的异同等前沿问题还有待于深入探索。申请人前期的研究工作筛选鉴定到阶段特异性调控NKT细胞分化成熟的表观遗传调控因子Np95和转录中介体Med19。本项目拟运用已经构建好的Np95和Med19条件敲除小鼠分析它们的缺失对于NKT细胞分化与功能的影响；结合DNA甲基化和RNA高通量测序结果阐明基因表达和表观遗传修饰调控NKT细胞分化过程中建立免疫功能和作用特性的分子机制；利用疾病模型研究NKT细胞分化异常对免疫应答及免疫相关疾病的调控与作用机制。力图揭示NKT细胞的分化成熟与功能特化的分子机制，为NKT细胞的临床应用提供理论基础。

Natural killer T (NKT) cells are a regulatory T cell lineage that participates in immune responses and a variety of immune diseases such as autoimmune disease, inflammation and tumor. Although much attention has been focused on the origin of NKT cells, the process of NKT cell development and function characterization, the molecular mechanism of NKT cell differentiation and the establishment of the accompanying acquisition of function is poorly understood. Our previous work revealed that the epigenetic regulator Np95 and the mediator subunit Med19 has specific roles in different stages of NKT cell development. By using the conditional knockout mice of Np95 and Med19, we plan to study the impact of Np95 and Med19 on NKT cell differentiation and function, respectively. Specially, we will try to study the epigenetic and transcriptional mechanisms by which Np95 and Med19 coordinately regulates the NKT cell differentiation and the accompanying acquisition of NKT function, and examine the impacts of Np95 and Med19 deficiencies on the immune responses and disease progression by using liver cancer and Listeria infection models. This project aims to uncover the regulation on the NKT development and function specification, and eventually lay theoretical basis for clinical trials in the future.