Kupffer Cells Support Hepatitis B Virus–Mediated CD8+ T Cell Exhaustion via Hepatitis B Core Antigen–TLR2 Interactions in Mice

Abstract

Hepatitis B virus (HBV) persistence is a fundamental process in chronic HBV infection and a key factor in all related liver diseases; however, the mechanisms have yet to be elucidated. We studied the role of TLR2 in HBV persistence using a well-established HBV-carrier mouse model generated by hydrodynamically injecting a phospho–adeno-associated virus/HBV1.2 plasmid into mice. We found that a genetic deficiency in TLR2 improves HBV elimination, whereas activating TLR2 led to more stable HBV persistence, suggesting that TLR2 activation is critical in HBV persistence. Furthermore, we noted that TLR2 activation could inhibit CD8+ T cell function, causing the exhaustion phenotype in HBV-carrier mice, because TLR2 deficiency might rescue CD8+ T cell function in a cellular adoptive experiment. TLR2 expression on Kupffer cells (KCs) was upregulated in HBV-carrier mice, which accounts for HBV persistence, because the difference in anti-HBV immunity between HBV-carrier wild-type and Tlr2−/− mice did not exist after KC depletion. In addition, similar to TLR2 deficiency, after KC depletion, CD8+ T cells were more efficiently activated in HBV-carrier mice, leading to rapid HBV elimination. KCs produced more IL-10 upon TLR2 activation in response to direct hepatitis B core Ag stimulation, and the elevated IL-10 inhibited CD8+ T cell function in HBV-carrier mice, because IL-10 deficiency or anti–IL-10R treatment resulted in CD8+ T cells with stronger antiviral function. In conclusion, KCs support liver tolerance by inducing anti-HBV CD8+ T cell exhaustion via IL-10 production after TLR2 activation by hepatitis B core Ag stimulation.

NK Cells Help Induce Anti–Hepatitis B Virus CD8+ T Cell Immunity in Mice

“…IL-10 can inhibit noncytolytic NK cell function in patients with acute HBV infection (48). In the chronic HBV-persistent model (6 mg plasmid/mouse) used in our laboratory, we previously observed that IL-10 played a key role in maintaining immune tolerance and that IL-10 deficiency or anti-IL-10R treatment resulted in stronger antiviral function of CD8 + T cells (27,49). These data also suggested that Kupffer cellderived IL-10 played a key role in reducing anti-HBV CD8 + T cell responses in an HBV-tolerant model.…”

Is chronic hepatitis B infection a protective factor for the progression of advanced pancreatic ductal adenocarcinoma? An analysis from a large multicenter cohort study

“…Several in vivo studies have found that NK cells, an important type of immune cells that reside in the liver sinusoids, can adhere to sinusoidal endothelial cells and Kupffer cells, therefore exerting its antimetastatic effect [34, 35]. Metastases of hematogenous tumor to the liver can also be inhibited by NKT cells stimulated with recombinant interleukin-12 (IL-12) [36]. Meanwhile, tumor growth in the liver can be inhibited by α -GalCer, inductor of bystander CD8+ CD122+ T cells and tumor-specific cytotoxic CD8+ T cells [36, 37].…”

Intrahepatic regulation of antiviral T cell responses at initial stages of viral infection

“…KCs can be activated by viral antigens via TLR2, resulting in increased IL-10 production [13, 48]. Elevated IL-10 in the liver suppresses the antiviral T cell activation and induce T cell exhaustion [13, 20, 49].…”

“…KCs can be activated by viral antigens via TLR2, resulting in increased IL-10 production [13, 48]. Elevated IL-10 in the liver suppresses the antiviral T cell activation and induce T cell exhaustion [13, 20, 49]. Importantly, KCs contribute to liver Treg cell-derived IL-10 production [20], and HBV particles also induce TGF-β production by KCs and probably promote Treg cell differentiation [50].…”