PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease
Abstract The specific mechanisms underlying effector pathways in autoimmune liver disease remain enigmatic and therefore constructing appropriate murine models to investigate disease pathogenesis becomes critical. A spontaneous severe murine model of autoimmune liver disease has been previously esta...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407284 |
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| author | Jie Long Si‐Yu Yang Zhen‐Hua Bian Hao‐Xian Zhu Min Ma Xiao‐Qing Wang Liang Li Weici Zhang Ying Han M. Eric Gershwin Zhe‐Xiong Lian Zhi‐Bin Zhao |
| author_facet | Jie Long Si‐Yu Yang Zhen‐Hua Bian Hao‐Xian Zhu Min Ma Xiao‐Qing Wang Liang Li Weici Zhang Ying Han M. Eric Gershwin Zhe‐Xiong Lian Zhi‐Bin Zhao |
| author_sort | Jie Long |
| collection | DOAJ |
| description | Abstract The specific mechanisms underlying effector pathways in autoimmune liver disease remain enigmatic and therefore constructing appropriate murine models to investigate disease pathogenesis becomes critical. A spontaneous severe murine model of autoimmune liver disease has been previously established in dnTGFβRII Aire−/− mice, exhibiting disease phenotypes that resemble both human primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The data suggests that auto‐reactive liver‐specific CD8+ T cells are the primary pathogenic cells in liver injury. In this study, these data are advanced through the use of both single‐cell sequencing and extensive in vitro analysis. The results identify a specific expanded pathogenic subset of PD‐1+CD8+ T cells in the liver, exhibiting strong functional activity and cytotoxicity against target cells. Depletion of PD‐1+CD8+ T cells using CAR‐T cells effectively alleviates the disease. GSDMD‐mediated pyroptosis is found to be aberrantly activated in the livers of model mice, and treatment with a GSDMD‐specific inhibitor significantly inhibits disease progression. In vitro experiments reveal that PD‐1+CD8+ T cells can induce the pyroptosis of hepatocytes through elevated production of granzyme B and perforin‐1. These results provide a novel explanation for the cytotoxic activity of pathogenic liver PD‐1+CD8+ T cells in autoimmune liver diseases and offer potential therapeutic targets. |
| format | Article |
| id | doaj-art-8fb12275f6654ad7b97e12bcd98c0078 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-8fb12275f6654ad7b97e12bcd98c00782025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202407284PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver DiseaseJie Long0Si‐Yu Yang1Zhen‐Hua Bian2Hao‐Xian Zhu3Min Ma4Xiao‐Qing Wang5Liang Li6Weici Zhang7Ying Han8M. Eric Gershwin9Zhe‐Xiong Lian10Zhi‐Bin Zhao11Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaGuangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaSchool of Biomedical Sciences and Engineering South China University of Technology Guangzhou International Campus Guangzhou 511442 ChinaSchool of Medicine South China University of Technology Guangzhou 510006 ChinaSchool of Medicine South China University of Technology Guangzhou 510006 ChinaSchool of Medicine South China University of Technology Guangzhou 510006 ChinaMedical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaDivision of Rheumatology, Allergy and Clinical Immunology University of California Davis Davis CA 95616 USAState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Air Force Military Medical University Xi'an 710000 ChinaDivision of Rheumatology, Allergy and Clinical Immunology University of California Davis Davis CA 95616 USAGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaMedical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 ChinaAbstract The specific mechanisms underlying effector pathways in autoimmune liver disease remain enigmatic and therefore constructing appropriate murine models to investigate disease pathogenesis becomes critical. A spontaneous severe murine model of autoimmune liver disease has been previously established in dnTGFβRII Aire−/− mice, exhibiting disease phenotypes that resemble both human primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The data suggests that auto‐reactive liver‐specific CD8+ T cells are the primary pathogenic cells in liver injury. In this study, these data are advanced through the use of both single‐cell sequencing and extensive in vitro analysis. The results identify a specific expanded pathogenic subset of PD‐1+CD8+ T cells in the liver, exhibiting strong functional activity and cytotoxicity against target cells. Depletion of PD‐1+CD8+ T cells using CAR‐T cells effectively alleviates the disease. GSDMD‐mediated pyroptosis is found to be aberrantly activated in the livers of model mice, and treatment with a GSDMD‐specific inhibitor significantly inhibits disease progression. In vitro experiments reveal that PD‐1+CD8+ T cells can induce the pyroptosis of hepatocytes through elevated production of granzyme B and perforin‐1. These results provide a novel explanation for the cytotoxic activity of pathogenic liver PD‐1+CD8+ T cells in autoimmune liver diseases and offer potential therapeutic targets.https://doi.org/10.1002/advs.202407284aireautoimmune liver diseasednTGFβRIIPD‐1+CD8+ T cellspyroptosis |
| spellingShingle | Jie Long Si‐Yu Yang Zhen‐Hua Bian Hao‐Xian Zhu Min Ma Xiao‐Qing Wang Liang Li Weici Zhang Ying Han M. Eric Gershwin Zhe‐Xiong Lian Zhi‐Bin Zhao PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease Advanced Science aire autoimmune liver disease dnTGFβRII PD‐1+CD8+ T cells pyroptosis |
| title | PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease |
| title_full | PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease |
| title_fullStr | PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease |
| title_full_unstemmed | PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease |
| title_short | PD‐1+CD8+ T Cell‐Mediated Hepatocyte Pyroptosis Promotes Progression of Murine Autoimmune Liver Disease |
| title_sort | pd 1 cd8 t cell mediated hepatocyte pyroptosis promotes progression of murine autoimmune liver disease |
| topic | aire autoimmune liver disease dnTGFβRII PD‐1+CD8+ T cells pyroptosis |
| url | https://doi.org/10.1002/advs.202407284 |
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