IL-21促进慢乙肝患者HBV-特异性CTL形成及机制研究

HBV-特异性CTL在清除慢性HBV感染中起着关键作用。但目前单一抗病毒治疗难以完全恢复患者体内HBV特异性细胞免疫反应。如何在有效抗病毒治疗后，提高患者体内特异性CTL抗病毒应答，特别是获得长效免疫记忆，是HBV治愈的关键。我们前期研究证实过继转移IL-21介导的HIV-特异性CTL，能抑制抗病毒治疗停药后的病毒反弹。结合文献进展，我们推测，IL-21在促进幼稚T细胞分化为HBV-特异性CTL的过程中发挥重要作用。本项目拟通过免疫学、原子力学、转录组和代谢组等技术手段，旨在研究：1）明确IL-21可以促进外周血幼稚T细胞分化为特异性CTL；2）揭示幼稚T细胞分化为效应细胞，抑制HBV复制的机制；3）探讨IL-21对调控免疫记忆形成和维持效应应答的作用机制。为实现慢乙肝功能性治愈提供新策略。

HBV-specific cytotoxic T lymphocytes (CTLs) play a critical role on eliminating chronic hepatitis B(CHB) virus infection. However, the HBV-specific CTLs responses are unable to fully recover from current single antiviral therapies. How to induce a robust, long-lived memory CTLs-mediated immunity is therefore a major issue in HBV treatment. Previously, we adoptively transferred IL-21 primed HIV-specific CTLs to viral rebounded macaques after ART interruption, which mediated viral control and acquired central memory phenotype. This suggested that IL-21 has importance for long-term immune protection. We now postulate a significant role for IL-21 boosted HBV-specific CTLs response among a naive T cell population. Thus, we intend to investigate: 1) IL-21 enhancement of Ag-specific CTLs response among a naive T cell population; 2) how naive CD8+ T cells differentiate into effector T cells, and exert anti-viral effects in CHB; 3) the mechanisms of IL-21-induced memory formation and effecter function, in terms of immunology, biomechanics, transcriptomics and metabolomics. These findings will provide new insights in functional cure strategies against CHB.