Abstract
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.
Highlights
Chronic hepatitis B (CHB) continuous to be a global health problem, with 296 million people affected worldwide.[1]
In a humanized mouse model, in which transplanted human hepatocytes were infected with hepatitis B virus (HBV), MHC class I (MHC I)-restricted HBV-specific T cells even led to undetectable serum levels of HBV surface antigen and HBV DNA,[10] a status that is described as functional cure.[11]
To be able to express and characterize our MHC class II (MHC II)-restricted HBV-specific T cell receptors (TCRs) in T cells, the respective TCR sequences were cloned into a retroviral vector, using codon-optimized variable a and b chain domains combined with murine constant domains (Figure 1B)
Summary
Chronic hepatitis B (CHB) continuous to be a global health problem, with 296 million people affected worldwide.[1]. When T cells vanished, a viral rebound could only be contained with an HBV entry inhibitor,[10] underlining the necessity for long-term persistence of anti-HBV immunity
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