Molecular Mechanisms Of Hepatitis B Viral Pathogenesis And Persistence

传统的T细胞和B细胞在HBV感染中起关键作用。相比之下，在先天免疫和适应性免疫之间的界面细胞，如NKT细胞的贡献仍然存在争议。NKT细胞以T细胞受体（TCR）限制的方式对CD1d呈递的脂质抗原作出反应，并在同源抗原识别后数小时内表现出明显的细胞因子分泌，这对其他先天（NK）和适应性免疫细胞（T和B细胞）的激活具有广泛的影响。NKT细胞在HBV感染中的作用尚不清楚。最近在肝病毒科感染和HBV患者的动物模型中进行的研究表明，NKT细胞在感染后的早期时间点就被激活。因此，土拨鼠肝炎病毒感染导致肝脏NKT细胞在48小时内浸润，这与IFN-&#947；分泌和暂时抑制病毒复制有关。这些发现与以下事实相一致：通过给药iNKT细胞抗原&#945；-半乳糖神经酰胺（αGalCer）对不变(i) NKT细胞进行药理学刺激，导致HBV转基因小鼠体内的病毒复制快速受到IFN-&#947；依赖性抑制。同样，一项对HBV感染潜伏期人类的研究表明，HBV感染后早期，外周血NK细胞水平升高与先天免疫激活一致。这些研究证明了病毒控制与NKT细胞活化之间的相关性。为了研究NKT细胞是否是控制HBV感染的重要检查点，我们研究了各种体外和体内HBV模型。

Conventional T and B cells play a crucial role in HBV infection. In contrast, the contribution of cells at the interface between innate and adaptive immunity such as NKT cells remains controversial. NKT cells respond in a T cell receptor (TCR)-restricted manner to lipid antigens presented by CD1d and exhibit pronounced cytokine secretion within hours of cognate antigen recognition, which enables broad effects on activation of other innate (NK) and adaptive immune cells (T and B cells). The role that NKT cells play in HBV infection is unclear. Recent studies in animal models of hepadnaviridae infection and HBV patients have demonstrated activation of NKT cells at very early time points following infection. Thus, infection with woodchuck hepatitis virus led to hepatic NKT cell infiltration within 48 hours, which correlated with IFN-γ secretion and temporary suppression of viral replication. These findings are in accordance with the fact that pharmacological stimulation of invariant (i) NKT cells by administration of the iNKT cell antigen α-galactosylceramide (αGalCer) led to rapid IFN-γ-dependent inhibition of viral replication in HBV transgenic mice. Similarly, a study of humans during the incubation phase of HBV infection demonstrated increased levels of peripheral NK cells in accordance with innate immune activation early after HBV infection. These studies demonstrate a correlation between viral control and NKT cell activation. To investigate whether NKT cells are an important checkpoint that contributes to control of HBV infection, we studied various in vitro and in vivo HBV models. We showed that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and lead to activation of natural killer T (NKT) cells. The absence of NKT cells, CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control. Our findings of an NKT cell response soon after HBV exposure are in accordance with other recent observations in humans and animal models of HBV and suggest that NKT cells are part of an early, important sensing system that activates the immune response leading to effective priming of HBV-specific adaptive immune cells that are required for viral clearance. Our data suggest that HBV is susceptible to a distinct type of immune recognition directly following infection which is important for subsequent immune clearance.