Evaluation of Intrahepatic Immune and Virological Mechanisms of Immunopathology in Chronic Hepatitis B Patients using Fine Needle Aspiration Biopsy

• Applicant: Dr. Shirin Nkongolo
• Subject Area: Immunology ; Virology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442362849

T cell exhaustion is a defining characteristic of chronic viral infection. There is arguably no other human disease that results in greater antigen-specific T cell exhaustion than chronic Hepatitis B virus (HBV) infection. A majority of patients are infected at birth. HBV is a DNA virus with a low mutation rate compared to other viruses such as hepatitis C virus (HCV) HCV or human immunodeficiency virus (HIV). Coupled with high virus and antigen load, chronic hepatitis B (CHB) patients display profound exhaustion of T cell immunity. The extreme exhaustion is highlighted in CHB patients with liver cancer, where the Gehring lab showed that even tumor antigen specific T cell responses were greater than HBV-specific responses . Mechanisms of T cell exhaustion have been defined in mouse models and translated to checkpoint inhibitor therapy. Anti-PD-1 therapy partially restores HBV-specific T cell immunity in vitro and may improve therapy in CHB patients. However, checkpoint inhibitor therapy elicits only a partial response because inhibitory receptor expression is only one of several factors governing T cell functionality. For CHB, restoration of T cell immunity during chronic infection means 1) overcoming T cell specific defects of exhaustion and 2) breaking the tolerogenic liver environment – obstacles familiar to cancer immunotherapy.Preliminary work in the Gehring lab investigated blood and liver samples from different patient cohorts to define distinct immune profiles during liver inflammation. Using single-cell RNA sequencing of liver biopsies, they identified a population of CD8 T cells with an activated tissue-resident transcriptional phenotype that was unique to patients with liver inflammation. The population expressed high levels of the inhibitory receptors PD-1, Tim-3 and Lag-3. In contrast to the inhibitory phenotype, this CD8 T cell population was the only one where the antiviral cytokine, IFN-γ, and cytotoxic effector, Fas ligand, were detectable. These data suggest that the environment during liver inflammation overrides inhibitory receptor expression, promoting T cell function. Therefore, we hypothesize that immunologic definition of hepatic flares in CHB patients will provide an immune profile capable of breaking liver tolerance. Defining the inflammatory environment has the potential to identify immunotherapeutic targets that could restore T cell function for immunotherapy of chronic viral infections or cancer. The proposed study will i) validate the phenotype of CD8 T cells corresponding to their genetic signature and determine if the CD8 T cell population is HBV-specific; ii) identify the resting population of T cells from which the activated CD8 T cell population arises and iii) define the inflammatory environment that drives the function of this CD8 T cell population. The goal is to target specific CD8 T cells for immunotherapy in the liver and to define an effective antiviral immune response.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Adam J Gehring, Ph.D.