组织定居记忆性CD8+T细胞介导自身免疫性肝炎肝内免疫反应的机制研究

我们发现自身免疫性肝炎（AIH）患者肠道菌群较正常人在多样性和结构方面存在显著变化，但与肝内炎症的因果关系尚不明确。组织定居记忆性CD8+T细胞（CD8+TRM）在AIH患者肝内显著增加，与肝内炎症和纤维化正相关。CD244基因在CD8+TRM呈特异性高表达，其配体CD48在AIH肝内炎症细胞中呈强阳性。肠道菌群产物可有效诱导肠道抗原提呈细胞（APC）和淋巴细胞表达CD244。我们提出科学假设：①CD8+TRM是AIH肝内炎症启动、维持和复发的重要免疫效应细胞；②CD244作为关键共刺激分子参与调控肝内CD8+TRM的发育与维持；③AIH相关肠道菌群产物通过上调APC表面的CD48和/或CD8+TRM表面的CD244，调控肝脏免疫微环境。本项目拟阐明CD8+TRM在AIH发病机制中的作用，探讨肠道菌群及其代谢物对CD8+TRM发育潜在调控机制，为AIH“肝病肠治”提供理论依据。

Our group has found gut microbiome of AIH had significant changes in diversity and composition compared with healthy controls. But the relationship between gut microbiome and intrahepatic inflammation was still not clear. The number of tissue resident memory CD8+ T cells (CD8+ TRM) significantly increased in AIH, and was positively correlated with the degree of inflammation and fibrosis. CD244 was highly expressed in CD8+ TRM, strikingly, its ligand CD48 was strongly positive in the inflammatory cells of AIH. Studies have shown that gut microbiome could effectively induce the expression of CD244 in intestinal antigen presenting cells (APC) and lymphocytes. Therefore, we propose the following three scientific hypotheses: ①CD8+ TRM cells play an important role in the development of AIH liver inflammation; ②As a key costimulatory molecule, CD244 is involved in the regulation of the development and maintenance of CD8+ TRM; ③AIH-associated gut microbiome or their metabolites could up-regulate the expression of CD48 on the APC or CD244 on the CD8+ TRM, which affects the immune microenvironment in AIH liver. This study intends to elucidate the role of CD8+ TRM in AIH pathogenesis, and specific clearance of CD8+ TRM may be a new therapeutic method. The potential regulatory mechanism of gut microbiome on the development of CD8+ TRM was also discussed, which provided a novel theoretical basis for AIH.