Abstract
Background & aims:
CD8+ T cells play a crucial role in antiviral immunity; however, hepatitis B virus (HBV)-specific CD8+ T cells become dysfunctional during chronic HBV (CHB) infection. Blocking inhibitory pathways only partially restores efficient antiviral responses, suggesting that the mechanism underlying CD8+ T-cell dysfunction is complicated. This study aimed to investigate whether HBV-specific CD8+ T cells undergo ferroptosis, examine its correlation with T-cell dysfunction, and elucidate the underlying mechanism and potential intervention strategies.
Methods:
Analysis of CD8+ T cells from patients with CHB revealed ferroptosis markers via flow cytometry, electron microscopy, and single-cell RNA sequencing, and HBV-specific CD8+ T cells were identified using HBV-core antigen peptide-loaded major histocompatibility complex I tetramer. Flow cytometry, single-cell RNA sequencing, and additional experimental approaches were employed to investigate the ferroptosis-associated mechanisms in CD8+ T-cell dysfunction.
Results:
Ferroptosis was observed in CD8+ T cells from patients with CHB, as indicated with increased lipid peroxidation, Fe2+ accumulation and mitochondrial atrophy, particular in HBV-specific CD8+ T cells. Downregulation of glutathione peroxidase 4 and upregulation of CD36 were found in CD8+ T cells with high level of lipid peroxidation. Furthermore, ferroptosis is accompanied by impaired antiviral ability. Mechanistically, palmitic acid upregulates CD36 expression, leading to lipid accumulation, whereas elevated serum transforming growth factor beta 1 in patients with CHB reduces GPX4 expression and impairs antioxidant capacity. These factors synergistically promote ferroptosis and dysfunction of CD8+ T cells. Treatment with selenium and liproxstain-1 enhanced cytotoxic cytokines production by CD8+ T cells, and subsequently improved antiviral efficacy in vivo.
Conclusions:
Our study demonstrates that ferroptosis drives CD8+ T-cell dysfunction in chronic HBV infection. Targeting ferroptosis pathways may offer a novel therapeutic strategy to restore antiviral immunity.