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-γsecretion 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.

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