Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Xu, Long; Yin, Wenwei; Sun, Rui; Wei, Haiming; Tian, Zhigang

doi:10.1073/pnas.1306437110

Cited by 42 publications

(40 citation statements)

References 38 publications

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“…Later on, the Chen group (22) established a mouse model of HBV persistence by hydrodynamic injection of the pAAV-HBV1.2 plasmid; this model was then used as a useful platform to study the mechanisms of local HBV-induced global immune tolerance in chronic infection, as recently evidenced by our group (26,27). Interestingly, in contrast to HBV persistence, we found that a high dose of pAAV-HBV1.2 plasmid injected into C57BL/6 WT mice caused rapid elimination of HBV from the liver, almost mimicking acute HBV infection (21).…”

Section: Resultsmentioning

confidence: 91%

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

Zheng¹,

Sun

Wei

et al. 2016

The Journal of Immunology

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Although recent clinical studies demonstrate that NK cell function is impaired in hepatitis B virus (HBV)–persistent patients, whether or how NK cells play a role in anti-HBV adaptive immunity remains to be explored. Using a mouse model mimicking acute HBV infection by hydrodynamic injection of an HBV plasmid, we observed that although serum hepatitis B surface Ag and hepatitis B envelope Ag were eliminated within 3 to 4 wk, HBV might persist for >8 wk in CD8−/− mice and that adoptive transfer of anti-HBV CD8+ T cells restored the ability to clear HBV in HBV-carrier Rag1−/− mice. These results indicate that CD8+ T cells are critical in HBV elimination. Furthermore, NK cells increased IFN-γ production after HBV plasmid injection, and NK cell depletion led to significantly increased HBV persistence along with reduced frequency of hepatitis B core Ag–specific CD8+ T cells. Adoptive transfer of IFN-γ–sufficient NK cells restored donor CD8+ T cell function, indicating that NK cells positively regulated CD8+ T cells via secreting IFN-γ. We also observed that NK cell depletion correlated with decreased effector memory CD8+ T cell frequencies. Importantly, adoptive transfer experiments showed that NK cells were involved in anti-HBV CD8+ T cell recall responses. Moreover, DX5+CD49a− conventional, but not DX5−CD49a+ liver-resident, NK cells were involved in improving CD8+ T cell responses against HBV. Overall, the current study reveals that NK cells, especially DX5+CD49a− conventional NK cells, promote the antiviral activity of CD8+ T cell responses via secreting IFN-γ in a mouse model mimicking acute HBV infection.

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Section: Resultsmentioning

confidence: 91%

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

Zheng¹,

Sun

Wei

et al. 2016

The Journal of Immunology

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“…Using this HBV-carrier mouse model, our previous studies demonstrated that KC-derived IL-10 induces type I regulatory T cells and subsequently maintains humoral immune tolerance. In addition, gdT cells drive myeloidderived suppressor cell-mediated CD8 + T cell exhaustion (5,11,23). In the current study, we observed that TLR2 on KCs plays a key role in HBV persistence by supporting CD8 + T cell exhaustion through the secretion of IL-10 upon interaction with HBcAg.…”

mentioning

confidence: 99%

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

Sun

et al. 2015

The Journal of Immunology

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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.

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“…Researchers co-cultured KCs and CD4+T cells, and found that KCs from mice infected with HBV could induce CD4+T cells to produce IL-10 and generate Tr1-like cells. 38 Thus it can be concluded that immune tolerance of HBV/HCV is partly achieved through the secretion of IL-10 by KCs.…”

Section: Il-10 and Tgf-βmentioning

confidence: 99%

Kupffer cell in the immune activation and tolerance toward HBV/HCV infection

Yuan¹,

Zhang²,

et al. 2017

Adv Clin Exp Med

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Kupffer cells (KCs) are macrophages that are found in the sinusoids of the liver. KCs are a crucial part of the innate immune system, acting as scavengers and phagocytes. KCs and sinusoidal endothelial cells together form the first immune barrier of the portal system. Studies show that KCs can not only maintain homeostasis in the immune response, but also facilitate the pathogenesis of type B and type C hepatitis (HBV/HCV) through their antigen-presenting function and secretion of soluble mediators. KCs can express toll-like receptors (TLRs), Fas ligand (FasL) and programmed cell death ligand 1 (PD-L1), and secrete large amounts of inflammatory factors leading to immune tolerance toward HBV/HCV. On the one hand, KCs contribute to the clearance of HBV/HCV due to their nature as innate immune cells. At the same time, KCs induce immune tolerance toward HBV/HCV, which leads to chronicity of the infection. The dual role of KCs in the immune response toward HBV/HCV means it is a gigantic challenge for scientists to illuminate the detailed mechanisms involved, but it also offers important potential therapeutic targets.

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Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Cited by 42 publications

References 38 publications

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

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

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

Kupffer cell in the immune activation and tolerance toward HBV/HCV infection

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