Hepatitis B virus antigens impair NK cell function

Yang, Yinli; Han, Qiuju; Zhang, Cai Fen; Xiao, Min; Zhang, Jian Cheng

doi:10.1016/j.intimp.2016.06.015

Cited by 38 publications

(39 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…43 However, rare studies assayed the interaction between HBsAg and NK cells. These limited data 44 Here, we present data supporting the importance of CD56 bright NK cells to HBsAg clearance via TRAIL and IFNγ/TNFα cytolytic and noncytolytic pathways. Importantly, enhanced CD56 bright NK numbers and functional activity may contribute to loss of HBV cccDNA ( Figure S4).…”

Section: Discussionsupporting

confidence: 51%

“…However, rare studies assayed the interaction between HBsAg and NK cells. These limited data indicated that HBsAg blocked NK cell activation, cytokine production and cytotoxic granule release in the human NK cell line NK‐92, which might be related to the downregulation of activating receptors and upregulation of inhibitory receptors. The current and previous studies in vitro or in vivo implied a cascade effect of HBsAg reduction and recovery of NK cells, in which PegIFNα treatment could break tolerance induced by high burden of HBsAg.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

Shi

Zhang

Xiao

et al. 2018

Journal of Viral Hepatitis

View full text Add to dashboard Cite

HBV surface antigen (HBsAg) reduction is well observed in chronic hepatitis B (CHB) patients treated with pegylated interferon alpha-2a (PegIFNα). However, the mechanism of HBsAg suppression has not been fully elucidated. Twenty-seven of 55 entecavir-treated CHB e antigen positive patients were switched to PegIFNα treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD56 /CD56 NK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co-cultured with HepAD38 cells for measurement of HBsAg, apoptosis and covalently closed circular DNA (cccDNA). In association with a reduction of HBsAg, the percentage and absolute number of CD56 NK cells was significantly elevated in patients in group A, especially in Virologic Responders (VRs, HBsAg decreased). Furthermore, the percentage of NKp30 , NKp46 , TRAIL , TNF-α and IFNγ CD56 NK cells were significantly expanded in Group A, which were positively correlated with the decline of HBsAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HBsAg in comparison with NK cells from Group B which was significantly inhibited by anti-TRAIL, anti-TNF-α and anti-IFNγ antibodies. Furthermore, apoptosis of HepAD38 cells and levels of cccDNA, were significantly reduced by TRAIL and TNF-α /IFNγ NK cells from Group A, respectively. A functional restoration of CD56 NK cells in entecavir-treated patients who were switched to PegIFNα contributes to HBsAg and cccDNA clearance through TRAIL-induced cytolysis and TNF-α/IFNγ-mediated noncytolytic pathways.

show abstract

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

Shi

Zhang

Xiao

et al. 2018

Journal of Viral Hepatitis

View full text Add to dashboard Cite

show abstract

“…To verify antiviral effects, we established the NK and HBV-HepG2 cells co-culture systems. However, because of the limited volumes of blood samples and the difficulty of in vitro amplification of detached primary NK cells, we were only able to use the cell line NK-92 as a succedaneum in this study 21, 22 . Activation of NK cells in chronic HBV infection is a “double-edged sword”: moderate activation is thought to be beneficial to breaking immune tolerance and balancing antiviral intensity, but excessive immune activation may cause pathological damage and thus increase the risk of liver failure 23, 24 .…”

Section: Discussionmentioning

confidence: 99%

NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection

Wang

Shen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Hepatitis B virus (HBV) infection is thought to be an immune-mediated liver disease. The mechanisms underlying natural killer (NK) cell group 2D receptor (NKG2D) that activates NK cells and participates in anti-HBV immunity and immunopathology has not been thoroughly elucidated. Peripheral NKG2D+ and IFN-γ+ NK cells frequencies and intrahepatic NKG2D and IFN-γ mRNA and protein expressions were determined in HBV-infected patients. Levels of NKG2D and IFN-γ mRNA and protein in NK cells, co-cultured with HBV-replicating HepG2 cells with or without NKG2D blockade, were analyzed. Serum and supernatant IFN-γ, TNF-α, perforin and granzyme B were measured. In results, peripheral NKG2D+ and IFN-γ+ NK cells frequencies, intrahepatic NKG2D and IFN-γ mRNA and protein levels, and serum IFN-γ, TNF-α, perforin and granzyme B levels were all highest in HBV-related acute-on-chronic liver failure group, followed by chronic hepatitis B and chronic HBV carrier groups. In vitro, NKG2D and IFN-γ mRNA and protein levels were higher in NK cells with IFN-α stimulation than without stimulation. Supernatant IFN-γ, TNF-α, perforin and granzyme B levels were increased under co-culture or IFN-α stimulating conditions, but were partially blocked by NKG2DmAb. In conclusion, NKG2D regulates immune inflammation and anti-viral response partly through activation of NK cells during HBV infection.

show abstract

“…In our previous study, we did not detect any HBV receptors like NTCP and ASGPR on the surface of NK cells. However, HBsAg bound to NK cell surface and suppressed STAT3 expression and phosphorylation at Tyr705, while that at Ser727 is known to be not influenced significantly by HBsAg . Tyr705 phosphorylation regulates STAT3 dimerization, nuclear translocation, and DNA binding, while phosphorylation at Ser727 induces transcriptional activation .…”

Section: Discussionmentioning

confidence: 98%

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients

Zheng

Yang

Han

et al. 2019

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

NK cells play an important role in early control of HBV infection. The function of NK cells is inhibited in chronic hepatitis B virus (CHB) infection, although the underlying mechanism remains unknown. We found that the expression of STAT3 decreased in peripheral NK cells of CHB patients, and was associated with low levels of degranulation and IFN-secretion. In addition, STAT3 levels were positively correlated with cytolysis-associated molecules and antiviral cytokines, such as CD107a, granzyme B, perforin, and IFN-. HBsAg directly inhibited the expression and activation of STAT3 in NK cells, and knocking down STAT3 expression in NK cells inhibited proliferation, decreased cyclin d1 levels, and suppressed responsiveness to IL-21 stimulation.Furthermore, STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. Taken together, our findings indicate that STAT3 is an important positive regulator of NK cells, and provide a new mechanism of NK cell dysfunction in CHB. K E Y W O R D SCD107a, CHB, granzyme B, IFN-, natural killer cells, NKp46, perforin, STAT3 INTRODUCTIONChronic hepatitis B virus (HBV) infection is a major health problem worldwide, and can trigger a wide spectrum of liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), which are altogether responsible for approximately 1 million deaths annually. 1 The aims of anti-chronic HBV (CHB) therapy are persistent suppression of viral replication, and the prevention of fibrotic progression and oncogenesis. 2 CHB is divided into the hepatitis B envelope Ag (HBeAg)-positive and HBeAg-negative phases. 2 The HBeAg + patients have demonstrated immune tolerance, and HBeAg seroconversion used to be the ideal endpoint of CHB therapy. 3,4 However, recent studies indicate that the HBeAg − CHB patients, including the inactive hepatitis B surface Ag (HBsAg) carriers, have a high risk of progressing to HCC, 5,6 and do not show any immune regulatory mechanism. 2 NK cells are crucial mediators of the innate immune system, and respond to viral infection rapidly without Ag presentation via the Abbreviations: CHB, chronic hepatitis B virus; EGF, epidermal growth factor; HBeAg, hepatitis B envelope Ag; HBsAg, hepatitis B surface Ag; HD, healthy donor; HGF, hepatocyte growth factor; HIES, hyper-IgE syndrome. MHC. 7,8 NK cell functions are regulated by several surface recognition receptors, with both activating and inhibitory functions, 9 which need to be maintained in a balanced state for proper NK cell response. Blocking the activating receptors NKp46 and DNAM-1 impaired NK cell cytotoxicity against cytomegalovirus-infected M s. 10 In CHB patients, the levels of activating receptors such as 2B4 and NKG2D were reduced by TGF-, while that of the inhibitory receptor NKG2A was elevated, resulting in dysfunctional IFN-production and NK cell cytotoxicity. 11-13 HBsAg sero-clearance by pegylated-IFN -2a and nucleos(t)ide analogues restored NK cell function in the HBeAgnegative ...

show abstract

Hepatitis B virus antigens impair NK cell function

Cited by 38 publications

References 35 publications

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients

Contact Info

Product

Resources

About

Hepatitis B virus antigens impair NK cell function

Cited by 38 publications

References 35 publications

CD56bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

CD56bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection

STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients

Contact Info

Product

Resources

About

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a