Dissecting antibody-mediated natural killer cell effects reveals a cytotoxic CX3CR1+KLRC2–CD16hi subset linked to hepatitis B virus outcomes
- Author:
Libo TANG
1
;
Yuhao WANG
;
Zihan JIN
;
Yurong GU
;
Zhaofeng ZENG
;
Linnan SONG
;
Xuan YI
;
Lingtao ZHANG
;
Yujing ZHANG
;
Weiying HE
;
Liping WANG
;
Weixin HE
;
Jianru SUN
;
Xiaoqin LAN
;
Xiangyong LI
;
Shihong ZHONG
;
Yongyin LI
Author Information
- Publication Type:Original Article
- From:Clinical and Molecular Hepatology 2026;32(2):683-705
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background/Aims:Natural killer (NK) cell function is generally considered dampened in chronic hepatitis B virus (HBV) infection; however, the NK cell pool exhibits phenotypic and functional heterogeneity, and the antibody--mediated effect of NK cells remains less characterized. This study evaluated the dynamic changes in antibody-mediated NK cell responses and the involvement of distinct NK subsets across disease stages and during antiviral treatment.
Methods:A T-cell receptor-like antibody specific for the HBV core 18–27 peptide (cTCRL-Ab) was used to determine the antibody-mediated effect of NK cells, and an array of NK cell surface markers were analyzed in cross-sectional and longitudinal cohorts of patients with chronic HBV infection. Single-cell RNA sequencing (scRNA-seq) was performed to identify the heterogeneity of NK subsets.
Results:The cTCRL-Ab enabled the detection of NK cell cytolytic activity and IFNγ production. Notably, cTCRL-Ab-mediated NK cell responses were compromised in chronically HBV-infected patients, particularly in those receiving pegylated interferon-α (Peg-IFNα), which was associated with the downregulation of CD16 expression. Correspondingly, Peg-IFNα inhibited cTCRL-Ab-mediated NK cell function by reducing CD16 expression in vitro. scRNA-seq revealed that CD16 downregulation occurred mainly within a dysfunctional CD16hi NK subset exhibiting exhaustion properties. In contrast, an activated CD16hiNK subpopulation (CX3CR1⁺KLRC2–CD16hi) with high cytotoxicity was enriched in patients who experienced favorable treatment responses. Furthermore, the intrahepatic CX3CR1+KLRC2–CD16hi subset tended to exhibit functional restoration in HBsAg-loss individuals.
Conclusions:Our data contribute to the understanding of antibody-mediated responses of NK cells in chronic HBV infection, and highlight a previously unappreciated functional CX3CR1+KLRC2–CD16hiNK subset as a potential therapeutic target.
