HBV特异性TNF-α+ CD4 Tscm新亚群 介导免疫损伤/保护的机制及干预策略研究

目前慢性HBV感染的功能治愈率不足1%，免疫调节干预策略是促进其功能治愈的核心问题。同行和我们前期研究提示，抗原特异性CD4+ T细胞通路在慢性HBV感染免疫损伤和免疫保护中发挥关键作用，但现有的T细胞免疫标签尚无法解释临床表型。我们前期发现了一类HBV特异性TNF-α+ T-bet- CD4 T细胞新亚群，其活化与重度肝损伤相关，且在抗原清除过程中向经典的产IFN-γ亚群转化。我们推测：TNF-α+ T-bet- CD4 T细胞很可能是Tscm早期亚群，适度活化后向Th1中晚期亚群（Tem/eff）分化促进免疫保护（抗原清除），过度活化和分化受阻则导致免疫损伤（肝炎活化）。本课题拟从患者队列、细胞、小鼠模型水平研究TNF-α+ T-bet- Tscm新亚群的免疫表型、发育及分化机制、免疫损伤/保护效应、干预策略，为有效恢复HBV保护性免疫、实现患者功能治愈提供新的干预策略和免疫学指标。

Chronic HBV infection is the top chronic viral infection of human in China, currently fewer than 1% of patients per year could actually be functionally cured. The key problem is how to activate a long-term immune response and achieve a functional cure for patients. Previous studies of ours and other groups demonstrated that antigen-specific CD4+ T cells plays an important role on immune injuries and immune protections during chronic HBV infection, however, there is lack of distinct T-cell-based immune signatures for clinical phenotypes. Recently we found a predominance of HBV-specific TNF-α+ T-bet- CD4 T cell subsets, which present an early stage (Tscm) , correlated with liver injury and could transform into classic IFN-γ-producing subsets during antigen clearance. Here we hypothesize that the TNF-α+ T-bet- CD4 T cell subsets could be Tscm (early subsets), they promote immune protections (viral antigen clearance) by activation and differentiation into Tem/eff (intermediate or late stage Th1 subsets), whereas their vigorous activation and differential blocking may cause immune injuries (hepatitis flare). In this project, we plan to study the immune phenotype, developmental and differential mechanisms, immune injury/protection effects and targeted intervention strategies of the novel TNF-α+ Tscm subsets based on cohort patients, in vitro culture and in vivo mice models. Our proof of concept studies may provide novel intervention strategies and immunological markers for the restoration of protective immunity and faster achievement for functional cures in chronic hepatitis B patients.