病毒特异性CD4+T细胞在慢加急性肝衰竭（ACLF）的免疫损伤中起重要作用。我们研究发现，HLA-DR是全基因组范围内影响HBV-ACLF免疫损伤的关键分子，提示HLA-DR抗原提呈信号的重要性。我们进一步鉴定出风险等位HLA-DRB1*12:02限制性的HBV表位肽，可刺激CD4+T细胞分泌产生大量的TNF-α，是可能的致炎表位肽，但功能效应及炎症启动机制尚不清楚。鉴于HLA-II类分子抗原提呈是CD4+T细胞活化的特异性第一信号，我们推测，新鉴定的表位肽可能通过DR抗原提呈信号促进CD4+T细胞活化及TNF-α+亚群分化，引发免疫损伤和肝炎活化。本研究拟从CD4+T细胞免疫效应和极化偏向、对抗原提呈细胞的反向调节、表位肽与DR的亲合力/稳定性、转基因小鼠模型等方面，明确HLA-DR限制性HBV表位介导CD4+T细胞活化的效应及机制，为ACLF免疫损伤关键始动环节提供新认识。

Acute-on-chronic liver failure (ACLF) is an acute severe exacerbation of chronic hepatitis B. Hepatitis B virus (HBV)-specific adaptive immune responses of CD4+ T cells play an important role during the immune-pathogenesis of ACLF, however, the detailed mechanisms of its triggering is unclear. Recently, we performed a genome-wide association study and identified the HLA-DRB1*12:02 as the top allele for HBV-related ACLF, which highlighted the importance for antigen-presentation via HLA-DR. This result had been published on Gut 2018. Furthermore, our group identified seven HLA-DRB1*12:02-specific restricted HBV epitope peptides and two draft epitope peptides in patients with chronic HBV infection, and found these peptides could stimulate CD4+ T cell proliferation and secretion of TNF-α and IFN-γ. It’s interesting that we found the TNF-α+ CD4+ T cells were associated with the hepatitis flare and injury in patients with severe hepatitis. All the results suggested that these new identified HBV epitope peptides may play a role as pro-inflammatory peptides in the activation of chronic hepatitis B, but how it works is not entirely clear. As the important role of antigen presentation by HLA class-II molecular in the CD4+ T cell adaptive immune response to the microbial pathogens, here we hypothesize the new identified HBV epitope peptides may promotes naïve CD4+ T cells activation and TNF-α-producing CD4 T cell subset differentiation by modulating the TCR-epitope-HLA-DRB1*12:02 signal, thus initiate start the adaptive immunity response and inflammatory in severe hepatitis. In this project, we plan to conduct serial experiments (the CD4+ T cell polarization via BLCL allele-specific presentation system, the affinity and stability of peptide-HLA-DR complex, inflammatory effects in HLA-DRB1*12:02 transgenic mouse models, etc.) and clarify the immune-pathogenesis of HLA-DRB1*12:02 restricted inflammatory epitopes. This study may provide new insights into the initiation of inflammatory in HBV-ACLF and new immunotherapy target of HBV-ACLF.