Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection
Elmira Aliabadi 1 2 3 , Melanie Urbanek-Quaing 1 2 3 , Benjamin Maasoumy 1 3 , Birgit Bremer 1 , Martin Grasshoff 4 , Yang Li 2 4 5 , Christian E Niehaus 1 2 , Heiner Wedemeyer 1 3 , Anke R M Kraft 1 2 3 , Markus Cornberg 6 2 3 5 7
Affiliations
Affiliations
1
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
2
TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany.
3
German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.
4
Computational Biology for Individualised Medicine, Helmholtz Centre for Infection Research (HZI), c/o CRC, Hannover, Germany.
5
Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany.
6
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany [email protected].
7
Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Hannover, Germany.
PMID: 34702717 DOI: 10.1136/gutjnl-2021-324646
Abstract
Objective: Hepatitis 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.
Design: We 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.
Results: HBV-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.
Conclusion: Our 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.