PD-1 signaling is essential for the early accumulation of HBV-specific CD8+ T cells during HBV infection

Background & Aims: Programmed cell death Protein 1(PD-1) is one of the key inhibitory receptors that regulates CD8 T cell exhaustion during chronic viral infection. However, the role of PD-1 in modulating effector T cell differentiation and function during early phase of hepatitis B virus (HBV) infection remains poorly defined. Methods: Using adoptive transfer of wild-type or PD-1 KO HBV-specific TCR transgenic (C93-TCRtg) CD8⁺ T cells, flow cytometry, and transcriptome sequencing, we systematically profiled early PD-1 dynamics in splenic and intrahepatic T cells and evaluated how PD-1 deficiency shapes anti-HBV T cell responses in acute self-resolving (AR) and chronic (CH) HBV mouse models. Results: Acute HBV infection induced sustained PD-1 upregulation on intrahepatic/splenic CD8⁺ T cells, which predominantly exhibited an effector phenotype. PD-1⁺ cells displayed enhanced proliferation, cytotoxicity, and effector cytokine production compared to PD-1⁻ counterparts. Adoptive transfer of PD-1 KO C93-TCRtg CD8⁺ T cells resulted in significantly impaired early expansion in both spleen and liver during acute infection, accompanied by reduced granzyme B expression while maintaining IFN-γ, TNF-α, or IL-2 production. Transcriptomic analysis revealed that PD-1 deficiency was associated with the upregulation of apoptosis gene signatures. In chronic HBV infection, PD-1 KO cells failed to expand long-term and exhibited exacerbated exhaustion evidenced by a loss of IFN-γ production. Conclusions: PD-1 is essential for the early expansion and survival of HBV-specific CD8⁺ T cells during acute infection and does not suppress their effector cytokine function. Its absence impairs proliferation and promotes exhaustion of HBV-specific CD8⁺ T cell in chronic infections.