The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.
Methods
98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.
Results
In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.
Conclusions
Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.
Abbreviations
HBV, hepatitis B virus;
HBeAg, hepatitis B e antigen;
HIV, human immunodeficiency virus;
PD-1, programmed cell death protein 1;
CTLA-4, cytotoxic T-lymphocyte protein 4;
2B4, natural killer cell receptor 2B4;
BTLA, B and T lymphocyte attenuator;
Tim-3, T cell immunoglobulin mucin receptor 3;
LCMV, lymphocytic choriomeningitis virus;
KLRG1, killer cell lectin-like receptor subfamily G member 1;
LAG-3, lymphocyte activation gene 3 protein;
MFI, median fluorescence intensity
Keywords
Virus-specific CD8+ T cells;
T cell differentiation;
T cell exhaustion;
HBV;
Inactive carrier;
PD-1;
Inhibitory receptors