Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection

Fumagalli, Valeria; Lucia, Pietro Di; Venzin, Valentina; Bono, Elisa; Jordan, Robert; Frey, Christian; Delaney, William E.; Chisari, Francis V.; Guidotti, Luca G.; Iannacone, Matteo

doi:10.1084/jem.20200298

Cited by 37 publications

(27 citation statements)

References 30 publications

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“…The results reported here are noteworthy considering that steady-state KC cross-presentation of HBV Ags is an inefficient process that cannot be increased by liver inflammation, hepatocellular death, or the administration of therapeutic monoclonal antibodies directed against HBsAg leading to the generation of circulating immune complexes ( Fumagalli et al., 2020 ). Our data do not rule out a direct effect of IL-2 on T cells; however, they indicate that optimal in vivo reinvigoration of intrahepatically primed T cells by IL-2 depends on the presence of KC2.…”

Section: Discussionmentioning

confidence: 88%

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

et al. 2021

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Section: Discussionmentioning

confidence: 88%

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

et al. 2021

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“…5 In contrast, another study showed that HBsAg clearance was not associated with increased antiviral T cell responses after interleukin-2-based immunotherapeutic intervention. 14 Understanding which viral and host factors are associated with the HBV-specific immune response, it is very important to identify biomarkers that can be used to select and stratify patients for clinical trials investigating novel therapeutic strategies aimed at functional cure. In addition to HBsAg, other viral proteins could potentially have an impact on the immune response.…”

Section: Hepatologymentioning

confidence: 99%

Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection

Aliabadi

Urbanek-Quaing

Maasoumy

et al. 2021

Gut

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ObjectiveHepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure.DesignWe analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core18-specific and polymerase (pol)455-specific CD8+ T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated.ResultsHBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4+ T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core18-specific and pol455-specific CD8+ T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg.ConclusionOur data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition.

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“…In order to determine the role of circulating and intrahepatic HBsAg in the induction of CD8+ T cell exhaustion, Fumagalli and colleagues reported recently that serum HBsAg clearance induced by either spontaneous seroconversion or therapeutic monoclonal antibodies has only a minimal effect on the expansion of HBV-specific naive CD8+ T cells undergoing intrahepatic priming (54). Interestingly, another study by this research group with transgenic mice expressing high level of HBcAg in almost all the hepatocytes and mice expressing lower level of HBcAg in approximately 10% of hepatocytes by adenoviral transduction showed that adoptively transferred HBcAg-specific naïve CD8+ T cells failed to differentiate into effector CTLs in mice expressing either high or low levels of HBcAg in hepatocytes (50).…”

Section: Effects Of Reducing Intrahepatic Viral Protein Expression And/or Circulating Hbsag On Antiviral Immune Responses In Mouse Modelsmentioning

confidence: 99%

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

Yang

Zeng

Zhang

et al. 2021

Emerging Microbes & Infections

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The prolonged viral antigen stimulation is the driving force for the development of immune tolerance to chronic hepatitis B virus (HBV) infection. The sustained reduction of viral proteins may allow for the recovery and efficient activation of HBV-specific T and B cells by immune stimulating agents, checkpoint blockades and/or therapeutic vaccinations. Recently, several therapeutic approaches have been shown to significantly reduce intrahepatic viral proteins and/or circulating HBV surface antigen (HBsAg) with variable impacts on the host antiviral immune responses in animal models or human clinical trials. It remains to be further investigated whether reduction of viral protein expression or induction of intrahepatic viral protein degradation is more efficacious to break the immune tolerance to chronic HBV infection. It is also of great interest to know if the accelerated clearance of circulating HBsAg by antibodies has a long term immunological impact on HBV infection and disease progression. Although it is clear that removal of antigen stimulation alone is not sufficient to induce the functional recovery of exhausted T and B cells, accumulating evidence suggests that the reduction of viral antigen load appears to facilitate the therapeutic activation of a functional antiviral immunity in chronic HBV carriers. Based on systematic review of the findings in animal models and clinical studies, the research directions toward discovery and development of more efficacious therapeutic approaches to reinvigorate HBV-specific adaptive immune function and achieve the durable control of chronic HBV infection, i.e., a functional cure, in the vast majority of treated patients are discussed.

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Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection

Cited by 37 publications

References 30 publications

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

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