表观遗传调控因子Uhrf1介导NKT细胞调控肝脏免疫耐受的作用与机制

NKT细胞是一类特殊的T细胞，同时表达T细胞受体和NK受体。NKT细胞主要分布在肝脏，在受到抗原刺激后，可以在短时间内分泌大量的细胞因子，是介导固有免疫和适应性免疫的桥梁。我们前期的研究结果显示，在敲除表观遗传调控因子Uhrf1后，非I型NKT细胞（II型NKT细胞、γδ NKT细胞等）过度活化，从而诱导肝脏自发自身免疫性肝炎，Uhrf1敲除小鼠存活时间只有3-4个月。借助此Uhrf1敲除小鼠模型以及临床病人样品，本项目将深入探讨Uhrf1介导NKT细胞调控肝脏免疫耐受的作用与机制，一方面从细胞层面研究Uhrf1缺失后如何影响不同NKT细胞在自身免疫性肝炎发生发展中的作用；另一方面从分子层面诠释Uhrf1调控不同NKT细胞功能的作用机制，并以此为基础，系统揭示NKT细胞在肝脏区域免疫中的作用及调控机制。

NKT cells represent a distinct lineage of T cells that coexpress a conserved T cell receptor (TCR) and natural killer (NK) receptors. NKT cells are abundant in the liver, which can secrete high levels of cytokines upon antigen stimulation and sequentially activate innate and adoptive immunity. Our primary results indicate that the non-type I NKT cells (including type II NKT cells and δ NKT cells) are hyper-activated in the absence of epigenetic regulator Uhrf1. Uhrf1 deficiency causes spontaneous autoimmune liver disease and Uhrf1 deficient-mice died with 3-4 months after birth. Based on this Uhrf1 deficient-mouse model and clinical samples, we will further investigate how epigenetic regulator Uhrf1 mediates NKT cells to control the liver immune tolerance, including indentifying which kind of NKT cell subsets and how such subsets can elicit spontaneous autoimmune liver disease when Uhrf1 is ablated, and exploring how Uhrf1 control the function and regulation of NKT cells in the liver immune tolerance, thus to figure out the role and the underlying mechanisms of NKT cells in the regulation of liver immunity.