Molecular Mechanisms Of Hepatitis B Viral Pathogenesis And Persistence

传统T、B细胞在乙肝病毒感染中起着至关重要的作用。相比之下，天然免疫和获得性免疫之间的交界处的细胞，如NKT细胞，其贡献仍存在争议。NKT细胞以T细胞受体(TCR)受限的方式对CD1d提呈的脂类抗原作出反应，并在识别同源抗原的几小时内表现出显著的细胞因子分泌，这使得对其他先天(NK)和获得性免疫细胞(T和B细胞)的激活具有广泛的作用。NKT细胞在乙肝病毒感染中的作用尚不清楚。最近对肝导航病毒科动物模型和乙肝患者的研究表明，NKT细胞在感染后的非常早的时间点被激活。因此，土拨鼠肝炎病毒感染后48小时内肝脏NKT细胞浸润，与干扰素分泌和暂时抑制病毒复制有关。这些发现与这样一个事实是一致的，即通过给予iNKT细胞抗原-半乳糖神经酰胺(GalCer)对不变(I)NKT细胞的药理刺激导致在乙肝转基因小鼠中依赖干扰素的病毒复制的快速抑制。同样，一项对人类在乙肝病毒感染潜伏期的研究表明，在乙肝病毒感染后早期，外周血自然杀伤细胞水平的增加与先天免疫激活相一致。这些研究表明，病毒控制和NKT细胞激活之间存在相关性。为了研究NKT细胞是否是控制乙肝病毒感染的重要关卡，我们研究了各种体外和体内的乙肝病毒模型。 我们发现，表达乙肝病毒的肝细胞产生内质网(ER)相关的内源性抗原脂，包括由乙肝病毒诱导的分泌型磷脂酶产生的溶血磷脂，并导致自然杀伤T(NKT)细胞的激活。缺乏NKT细胞、CD1d或雌激素受体相关的脂类转移到CD1d的缺陷会导致乙肝病毒特异性T和B细胞反应减弱和病毒控制延迟。 我们对暴露于乙肝病毒后不久的NKT细胞反应的发现与最近在人类和动物模型中观察到的乙肝病毒的其他结果一致，并表明NKT细胞是早期重要的传感系统的一部分，该系统激活免疫反应，从而有效地启动病毒清除所需的乙肝病毒特异性适应性免疫细胞。我们的数据表明，在感染后，乙肝病毒对一种不同类型的免疫识别很敏感，这对随后的免疫清除很重要。

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.