{"entity": "publication", "iuid": "578ca6bc5b384c5aaccb8a95b1ffea8f", "timestamp": "2026-08-22T06:58:28.800Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/578ca6bc5b384c5aaccb8a95b1ffea8f.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/578ca6bc5b384c5aaccb8a95b1ffea8f"}}, "title": "NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis.", "authors": [{"family": "Huang", "given": "Bingyuan", "initials": "B"}, {"family": "Lyu", "given": "Zhuwan", "initials": "Z"}, {"family": "Qian", "given": "Qiwei", "initials": "Q"}, {"family": "Chen", "given": "Yong", "initials": "Y"}, {"family": "Zhang", "given": "Jun", "initials": "J"}, {"family": "Li", "given": "Bo", "initials": "B"}, {"family": "Li", "given": "Yikang", "initials": "Y"}, {"family": "Liang", "given": "Jubo", "initials": "J"}, {"family": "Liu", "given": "Qiaoyan", "initials": "Q"}, {"family": "Li", "given": "You", "initials": "Y"}, {"family": "Chen", "given": "Ruiling", "initials": "R"}, {"family": "Lian", "given": "Min", "initials": "M"}, {"family": "Xiao", "given": "Xiao", "initials": "X"}, {"family": "Miao", "given": "Qi", "initials": "Q"}, {"family": "Wang", "given": "Qixia", "initials": "Q"}, {"family": "Fang", "given": "Jingyuan", "initials": "J"}, {"family": "Lian", "given": "Zhexiong", "initials": "Z"}, {"family": "Li", "given": "Yanmei", "initials": "Y"}, {"family": "Tang", "given": "Ruqi", "initials": "R"}, {"family": "Helleday", "given": "Thomas", "initials": "T"}, {"family": "Gershwin", "given": "M Eric", "initials": "ME"}, {"family": "You", "given": "Zhengrui", "initials": "Z"}, {"family": "Ma", "given": "Xiong", "initials": "X"}], "type": "journal article", "published": "2022-11-00", "journal": {"title": "J Hepatol", "issn": "1600-0641", "volume": "77", "issue": "5", "pages": "1311-1324", "issn-l": null}, "abstract": "Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC.\n\nPhenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model.\n\nIntrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGF\u03b2R axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGF\u03b2-Smad signaling.\n\nCD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC.\n\nPrimary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.", "doi": "10.1016/j.jhep.2022.06.014", "pmid": "35753523", "labels": [], "xrefs": [{"db": "pii", "key": "S0168-8278(22)00408-1"}], "notes": [], "created": "2026-08-20T07:59:06.453Z", "modified": "2026-08-20T07:59:06.485Z"}