Using novel Tg mouse models, Xu et al. identified a TCR specific for a clinically relevant epitope rarely expressed on CD8+ T cells in chronic HBV infection. Efficacy of the specific TCR+ CD8+ T cells in a murine chronic HBV infection model was restrained by the immunosuppressive liver environment. Genome-wide CRISPR-Cas9 KO screening identified the mediator of such T cell restraint as ankyrin repeat domain11 (Ankrd11), a chromatin regulator that acts to break AP-1 family gene transcription. Ankrd11 deficiency in T cells boosted T cell expansion and differentiation of TPEX and PD-1-TOX- tolerant cells into effectors of murine antiviral and antitumor responses.
Contributed by Paula Hochman
ABSTRACT: CD8(+) T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8(+) T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8(+) T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1(-)TOX(-) tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.
Author Info: (1) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Acad
Author Info: (1) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (2) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. (3) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (4) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (5) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (6) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (7) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (8) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. Medical School, University of Chinese Academy of Sciences, Beijing, China. (9) Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, China. (10) Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China. wuhm2000@sina.com. HBV Infection, Clinical Cure and Immunology Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. wuhm2000@sina.com. Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China. wuhm2000@sina.com. (11) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. zhouxy@im.ac.cn. Medical School, University of Chinese Academy of Sciences, Beijing, China. zhouxy@im.ac.cn.
