CD16+ γδ T cells mediate antibody-dependent cellular cytotoxicity and associate with viral control in chronic hepatitis B virus infection
Schröter P, Steppich K, Fernández Carrera L, Song Z, Klein S, Souleiman R, Urbanek-Quaing M, Lietzau A, Schnieders A, Freyer E, Bremer B, León-Lara X, Almeida V, Gutierrez Jauregui R, Von Kaisenberg C, Bruhn M, Meineke C, Kalinke U, Wedemeyer H, Prinz I, Ravens S, Carpentier A, Bartsch Y, Kraft A, Cornberg M
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Gut, Page gutjnl-2025-337640
Abstract
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.
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