Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection

Yang, Feifei; Yu, Xueping; Zhou, Chenliang; Mao, Richeng; Zhu, Mengqi; Zhu, Haoxiang; Ma, Zhenxuan; Mitra, Bidisha; Zhao, Gan; Huang, Yuxian; Guo, Haitao; Wang, Bin; Zhang, Jiming

doi:10.1371/journal.ppat.1007690

Cited by 63 publications

(64 citation statements)

References 40 publications

(58 reference statements)

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“…However, which cells in the spleen that are primarily responsible for HBeAg-increased TGF-β production requires further investigation. The present data suggest that HBV exploits immune cells to create an TGF-β-rich microenvironment for peripheral Treg differentiation and HBV persistence, and are consistent with the notion that HBeAg can condition innate immune cells into anti-inflammatory types (34,35).…”

Section: Discussionsupporting

confidence: 89%

Hepatitis B envelope antigen increases Tregs by converting CD4+CD25‑ T cells into CD4+CD25+Foxp3+ Tregs

et al. 2020

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Hepatitis B virus (HBV) can establish a lifelong chronic infection in humans, leading to liver cirrhosis, liver failure and hepatocellular carcinoma. Patients with chronic hepatitis B (CHB) exhibit a weak virus-specific immune response. Regulatory T cells (Tregs) play a key role in regulating the immune response in patients with CHB. Patients with hepatitis B envelope antigen (HBeAg)-positive CHB harbored a higher percentage of Tregs in their peripheral blood than those with HBeAg-negative CHB. However, whether and how HBeAg manipulates the host immune system to increase the population of Tregs remains to be elucidated. The present manuscript describes a preliminary immunological study of HBeAg in a mouse model. Multiple potential CD4 + T cell epitopes in HBeAg were identified using Immune Epitope Database consensus binding prediction. It was demonstrated that HBeAg treatment increased the numbers of Tregs in mouse spleens in vitro and in vivo. Furthermore, it was indicated that the HBeAg-mediated increase in Tregs occurred through the conversion of CD4 + CD25-T cells into CD4 + CD25 + Foxp3 + Tregs. Additionally, in vitro study illustrated that HBeAg stimulated murine spleen cells to produce increased transforming growth factor-β, which is required to enable HBeAg to convert T cells into Tregs. The results of the present study may provide further evidence of the effect of HBeAg on Tregs and aid in the development of novel HBeAg-based immunotherapy for CHB.

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Section: Discussionsupporting

confidence: 89%

Hepatitis B envelope antigen increases Tregs by converting CD4+CD25‑ T cells into CD4+CD25+Foxp3+ Tregs

et al. 2020

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“…Although MDSCs have been reported to associate with protective functions in the context of acute liver inflammation, these cells seem to facilitate inflammation and tissue damage during chronic liver diseases. It was reported that HBV induces the expansion and activation of MDSCs [25], which favors T cell exhaustion. This leads to the establishment of persistent HBV infection and the maintenance of chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma

Zhang

et al. 2020

BioMed Research International

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Background and Aim. Myeloid-derived suppressor cells (MDSCs) have attracted attention due to their important role in tumor immune escape. Several studies have investigated the involvement of MDSCs into hepatocellular carcinoma (HCC); however, due to the difference of MDSC phenotype, patient types, and sample source among the studies, the results were inconsistent and controversial. The present study aimed to confirm the expression and clinical significance of MDSCs in HBV-related HCC patients. Methods. The percentages of MDSCs, IFN-γ-producing CD4 and CD8 T cells in the peripheral blood of HCC patients, chronic hepatitis B (CHB) patients, and healthy controls (HC) were determined by flow cytometry. The serum concentrations of IL-10 and TNF-α were determined by ELISA. The association of the percentages of MDSCs with tumor burden, liver function parameters, systemic inflammation-related indexes, and IFN-γ-producing T cells was assessed. Results. The percentages of MDSCs and PMN-MDSCs were significantly higher in HCC patients than those in CHB patients and HC. The level of MDSCs was correlated with indirect bilirubin and prealbumin, as well as systemic inflammation response index, monocyte/lymphocyte ratio, and monocyte counts. The frequency of IFN-γ-producing CD8 T cells of HCC patients was lower than that of HC. However, there was no relationship between MDSCs and IFN-γ-producing CD8 T cells. The level of IL-10 in HCC patients was significantly higher than that in CHB patients. Conclusion. MDSCs seem to play an important role in the process leading from chronic HBV infection to HCC. Early inhibiting these cells could affect tumor progression.

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“…Arginine depletion leads to reduction of CD3ζ levels in T cells, subsequently causing TCR-pathway dysfunction (36). Intrahepatic inflammation recruits regulatory T cells (37-41), B cells, and myeloid-derived suppressor cells (42)(43)(44), and activate stellate cells, leading to IL-10 and TGF-β production (25). The suppressive events in the liver are vital for protection from severe damage primed by inflammation, while further impairing the functionality of HBV-specific T cells.…”

Section: Immune Pathogenesis Of Persistent Hbv Infectionmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection

Cited by 63 publications

References 40 publications

Hepatitis B envelope antigen increases Tregs by converting CD4+CD25‑ T cells into CD4+CD25+Foxp3+ Tregs

Hepatitis B envelope antigen increases Tregs by converting CD4+CD25‑ T cells into CD4+CD25+Foxp3+ Tregs

Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

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