Background Chronic hepatitis B virus (HBV) infection is characterised by immune dysfunction. While conventional T cell responses have been extensively studied, the role of γδ T cells, innate-like cytotoxic lymphocytes enriched in the liver, remains incompletely understood. Objective To characterise γδ T cell subsets in HBV infection and assess their association with viral control and antibody-dependent cellular cytotoxicity (ADCC). Design Peripheral blood from patients with chronic (n=83) and acute (n=16) HBV infection, healthy controls (n=31), and cord-blood donors (n=3) was analysed using multiparameter flow cytometry, single-cell RNA sequencing and in vitro ADCC assays. Results A distinct CD16 + γδ T cell subset inversely correlated with hepatitis B core-related antigen (HBcrAg), a surrogate of intrahepatic viral replication. CD16 + γδ T cells displayed a cytotoxic signature, whereas CD16⁻ cells showed inflammatory, non-cytotoxic profiles. On hepatitis B surface antigen-specific antibody stimulation, CD16 + γδ T cells mounted potent ADCC responses, mainly mediated by Vδ2 + cells expressing the activating receptor CD226, while Vδ1 + cells preferentially expressed the inhibitory receptor TIGIT. Cytotoxic CD16 + Vδ2 + γδ T cells were present in both blood and liver. CD16 + γδ T cells were expanded and highly functional in acute HBV but reduced and partially impaired in chronic infection. Neonatal cord-blood-derived γδ T cells lacked CD16 expression and displayed limited ADCC potential. Conclusions CD16 + γδ T cells mediate antibody-dependent antiviral immunity in HBV infection. Their inverse association with HBcrAg links γδ T cell-mediated ADCC to viral control and highlights this pathway as a target for HBV cure strategies.
Schröter et al. (Wed,) studied this question.