肝脏是特殊的免疫器官。在嗜肝病毒中，HBV是非致细胞病变病毒，HBV感染是典型的免疫清除而痊愈、免疫损伤而致病、免疫耐受而携带。已有研究提示：肝脏局部细胞免疫在病毒清除具有核心作用，但造成上述不同后果的机制不清。本课题组拟在肝脏免疫及HBV感染免疫研究取得重要进展的基础上，在人体阐明肝脏HBV感染免疫库及其形成、维持机理。①基于HBeAg、HBsAg血清学转阴与否、转阴前后的临床前瞻性随访队列及健康对照，采用免疫组学技术，比较肝内、循环中CD8+T细胞库，阐明相关保护性免疫亚库、损伤性亚库。②基于上述队列肝穿样本库，采用肝脏免疫系统定量病理、单细胞测序及功能试验，阐明保护性、损伤性免疫亚库形成和维持的肝脏先天免疫系统调节机制。③在“孪生子感染不同临床后果”队列和小鼠模型，验证上述机制。旨在阐明HBV感染免疫库，阐述其形成、维持的肝脏局部规则，为临床治疗和发展治疗性疫苗的探索新的靶标。

The liver is a special immune organs. HBV is a non-cytopathic virus. For hepatitis induced by HBV infection, both viral clearance and immune damage are mediated by immunity. Previous studies indicated that local cellular immune response in liver plays a central role in virus clearance, but the mechanism is unclear. Gained enlightenment from our research progress on HBV infection immunity, we intend to elucidate the virus clearance related protective T cell repertoire and mechanism for its formation and maintenance. ① Based on long-term follow-up cohorts of patients with and without seroconversion of HBeAg or HBsAg, along with a validation cohort and a healthy control cohort, we define the HBeAg or HBsAg seroconversion-related subrepertoire by separately comparing the peripheral and/or intrahepatic T cell repertoire obtained by high throughput sequencing of TCR, immunoinformatics and system immunology techniques. In vivo intervention experiments regarding immunoinformatics analysis indicated repertoire-related viral antigens, immunoregulatory molecules are employed to investigate the factors and mechanisms for activation and persistence of the subrepertoire. ② By using whole slide image, single cell RNA-seq and in vitro assay, we will study the relationship between liver innate immune system and the formation of protective or harmful sub-repertoire. ③ Further , based on twins cohorts with different clinical consequences of HBV infection, the mechanism of viral clearance will be validated by same protocol. For the first time, this study will clarify the mechanism of protective immunity in terms of local T cell repertoire, and will provide new targets for clinical treatment and development of therapeutic vaccines.