CD16+ γδ T Cells: A Novel Player in HBV Viral Control Through Antibody-Dependent Cytotoxicity

Highlights

1. CD16+ γδ T cells exhibit potent antibody-dependent cellular cytotoxicity (ADCC) against HBV, inversely correlating with viral replication markers like HBcrAg.

2. Vδ2+ γδ T cells express activating receptor CD226, enhancing ADCC, while Vδ1+ cells show inhibitory TIGIT expression, suggesting a regulatory balance.

3. Acute HBV infection features expanded, functional CD16+ γδ T cells, whereas chronic infection shows reduced and impaired subsets, hinting at immune exhaustion.

Background

Chronic hepatitis B virus (HBV) infection affects over 250 million globally, with immune dysfunction central to its persistence. While conventional T cells are well-studied, γδ T cells—innate-like lymphocytes abundant in the liver—remain underexplored despite their cytotoxic potential. This study investigates their role in viral control via ADCC, a mechanism where immune cells target antibody-coated infected cells.

Study Design

The study analyzed peripheral blood from 83 chronic and 16 acute HBV patients, 31 healthy controls, and 3 cord-blood donors. Methods included multiparameter flow cytometry, single-cell RNA sequencing, and in vitro ADCC assays using hepatitis B surface antigen (HBsAg)-specific antibodies.

Key Findings

CD16+ γδ T Cells and Viral Control

CD16+ γδ T cells displayed an inverse correlation with HBcrAg, a surrogate for intrahepatic viral replication. Single-cell RNA sequencing revealed a cytotoxic signature in CD16+ subsets, contrasting with inflammatory profiles in CD16⁻ cells.

ADCC Mechanisms

Upon HBsAb stimulation, CD16+ γδ T cells, particularly Vδ2+ subsets, mounted robust ADCC responses via CD226 activation. Vδ1+ cells, however, expressed inhibitory TIGIT, suggesting a nuanced regulatory interplay.

Clinical Implications

Acute HBV cases showed expanded, functional CD16+ γδ T cells, while chronic patients had diminished subsets with impaired cytotoxicity. Neonatal cord blood lacked CD16+ γδ T cells, underscoring their acquired role in antiviral immunity.

Expert Commentary

“This study bridges a critical gap in HBV immunology by linking γδ T cell-mediated ADCC to viral control,” notes Dr. Heiner Wedemeyer, a co-author. The findings align with emerging evidence that non-classical lymphocytes contribute substantially to HBV immunity.

Conclusion

CD16+ γδ T cells emerge as pivotal effectors in HBV clearance via ADCC, offering a novel target for immunotherapies. Their dysfunction in chronic HBV highlights a pathway to address in cure strategies. Future research should explore boosting these cells therapeutically.

Funding

Supported by the German Research Foundation (DFG) and the Helmholtz Association. ClinicalTrials.gov identifier: Not provided.