CD300A CD8 T Cells as Predictive Biomarkers for Achieving Functional Cure in Chronic Hepatitis B Patients Undergoing Pegylated Interferon-Alpha Therapy.

Background & Aims: Pegylated interferon-alpha (PEG-IFN-α) is the first choice for achieving functional cure (FC) in chronic hepatitis B (CHB), but only about 30% of patients achieve this outcome within a defined treatment duration. Given the critical role of CD8 T cells as antiviral effectors, we investigated their changes during FC to identify novel predictive markers of treatment efficacy.

Methods: We enrolled CHB patients with serum HBsAg levels < 3000 IU/mL in a discovery cohort and collected their peripheral blood mononuclear cells after PEG-IFN-α therapy. We used single-cell transcriptome profiling coupled with T cell receptor (TCR) sequencing and flow cytometry to assess CD8 T cell immune characteristics. Findings were validated longitudinally by flow cytometry in an independent cohort receiving PEG-IFN-α therapy.

Results: In FC patients, CD8 T cell subsets exhibited distinct transcriptional profiles. c04 (Temra/Teff) and c06 (proliferating T) showed significant clonal expansion compared to non-FC patients. CD300A expression was highly enriched in FC cells, correlating with cytotoxicity-related gene signatures (e.g., GZMB, GNLY, PRF1). CD300A CD8 T cells demonstrated greater clonal expansion, enhanced antigen reactivity and a transcriptional network driven by TBX21 and EOMES, with enrichment of HBV-specific CD8 T cells. Longitudinal validation confirmed that baseline CD300A CD8 T cells, particularly non-naive subsets, were associated with greater HBsAg decline and earlier FC, independent of baseline HBsAg levels.

Conclusions: CD300A CD8 T cells are enriched in patients achieving FC during PEG-IFN-α therapy, exhibiting robust clonal expansion, enhanced cytotoxicity and HBV antigen specificity. These cells may serve as potential biomarkers for treatment response to improve FC rates in CHB therapy.