Characterization and functional modulation of HBV-specific CD4+ T cell responses

Background and aims:

CD4+ T cells are central regulators of both humoral and cellular immunity. In the context of chronic HBV-infection, HBV-specific CD4 T cells are reduced in numbers and functionally impaired. Since current therapies fail to offer a cure from chronic HBV-infection, novel therapeutic concepts involving immunotherapy are desperately needed. The functional modification of HBV-specific CD4+ T cells may represent a promising approach to improve immunotherapeutic strategies.

Methods:

In order to identify and comprehensively characterize HBV-specific CD4 T cells we expanded PBMCs from chronic HBV patient samples (n = 70) with a pool of overlapping peptides spanning the whole HBV polyprotein followed by flow cytometric analysis for interferon gamma secretion. In parallel, we identified CD4+ T cell responses to Epstein-Barr-virus, influenza A and tetanus toxoid in healthy donors (n = 60). Currently, the addition of agonistic reagents to co-stimulatory receptors and blocking reagents to inhibitory receptors during in vitro culture is analyzed to identify pathways that could improve functionality of HBV-specific CD4+ T cells.

Results:

HBV-specific CD4+ T cell responses were detected in 32% of chronically infected patients, mostly targeting the viral polymerase- and core-antigen region, but not the surface antigen. We are currently evaluating the capacity of inhibitory receptor blockade, addition of cytokines and co-stimulatory molecules to improve the functionality and transcriptional profile of HBV-specific CD4+ T cells and CD4+ T cell responses to control peptides. Our preliminary data suggest a pathogen-specific responsiveness to different culture conditions in vitro.

Discussion:

Understanding the lack of HBV surface antigen-specific CD4+ T-cell responses as well as the identification of pathways that positively influence the antiviral capacities of HBV-specific CD4+ T cells could contribute to the development of a CD4+ T cell based immunotherapy for HBV infection.

Corresponding author: Boettler, Tobias

E-Mail: [e-mail]