Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2
Abstract CD4+Foxp3+ regulatory T cells are essential for maintaining immune tolerance and preventing excessive inflammation, making them promising candidates for treating autoimmunity and GvHD. However, the translation of regulatory T cell therapy into clinical practice poses substantial challenges....
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62628-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849233946173243392 |
|---|---|
| author | Hao Cheng Fang Nan Ning Ji Xiao Ma Jianan Zhang Hantian Liang Wei Zhang Hiroko Nakatsukasa Huiyuan Zhang Wenwen Jin Hong Jiang Jiyu Tong Xikun Zhou Ning Li Qi Zhang Hongbo Hu WanJun Chen Hao Xu Dunfang Zhang |
| author_facet | Hao Cheng Fang Nan Ning Ji Xiao Ma Jianan Zhang Hantian Liang Wei Zhang Hiroko Nakatsukasa Huiyuan Zhang Wenwen Jin Hong Jiang Jiyu Tong Xikun Zhou Ning Li Qi Zhang Hongbo Hu WanJun Chen Hao Xu Dunfang Zhang |
| author_sort | Hao Cheng |
| collection | DOAJ |
| description | Abstract CD4+Foxp3+ regulatory T cells are essential for maintaining immune tolerance and preventing excessive inflammation, making them promising candidates for treating autoimmunity and GvHD. However, the translation of regulatory T cell therapy into clinical practice poses substantial challenges. Here, we show that adoptive regulatory T cell therapy increases IL-6 and TGF-β-dependent pathogenic Th17 cell differentiation in murine models of inflammatory bowel disease and experimental autoimmune encephalomyelitis. Regulatory T cells increase the p-stat3/p-stat5 ratio in effector T cells by suppressing IL-2 secretion and competitively consuming IL-2, thereby promoting Th17 cell differentiation. Notably, IL-2 signaling deficiency not only promotes a Th17 cell-associated transcriptional program, but also enhances the pro-inflammatory properties of Th17 cells. Strikingly, therapeutic blockade of IL-6/STAT3 signaling pathway can reverse pathogenic Th17 cell differentiation and enhance the therapeutic effect of regulatory T cell therapy. Thus, our findings could potentially advance the clinical research progress of adoptive regulatory T cell therapy. |
| format | Article |
| id | doaj-art-d24338b8644b441d971fd456fa8ca4d0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d24338b8644b441d971fd456fa8ca4d02025-08-20T04:03:18ZengNature PortfolioNature Communications2041-17232025-08-0116112010.1038/s41467-025-62628-7Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2Hao Cheng0Fang Nan1Ning Ji2Xiao Ma3Jianan Zhang4Hantian Liang5Wei Zhang6Hiroko Nakatsukasa7Huiyuan Zhang8Wenwen Jin9Hong Jiang10Jiyu Tong11Xikun Zhou12Ning Li13Qi Zhang14Hongbo Hu15WanJun Chen16Hao Xu17Dunfang Zhang18Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityLaboratory of Microbiology and Immunology, Graduate School of Pharmaceutical SciencesCenter for Immunology and Hematology, Department of Biotherapy and Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityMucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent DriveDepartment of Pancreatic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Immunology, West China School of Basic Medical Sciences and Forensic Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of MedicineCenter for Immunology and Hematology, Department of Biotherapy and Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityMucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent DriveState Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityDepartment of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan UniversityAbstract CD4+Foxp3+ regulatory T cells are essential for maintaining immune tolerance and preventing excessive inflammation, making them promising candidates for treating autoimmunity and GvHD. However, the translation of regulatory T cell therapy into clinical practice poses substantial challenges. Here, we show that adoptive regulatory T cell therapy increases IL-6 and TGF-β-dependent pathogenic Th17 cell differentiation in murine models of inflammatory bowel disease and experimental autoimmune encephalomyelitis. Regulatory T cells increase the p-stat3/p-stat5 ratio in effector T cells by suppressing IL-2 secretion and competitively consuming IL-2, thereby promoting Th17 cell differentiation. Notably, IL-2 signaling deficiency not only promotes a Th17 cell-associated transcriptional program, but also enhances the pro-inflammatory properties of Th17 cells. Strikingly, therapeutic blockade of IL-6/STAT3 signaling pathway can reverse pathogenic Th17 cell differentiation and enhance the therapeutic effect of regulatory T cell therapy. Thus, our findings could potentially advance the clinical research progress of adoptive regulatory T cell therapy.https://doi.org/10.1038/s41467-025-62628-7 |
| spellingShingle | Hao Cheng Fang Nan Ning Ji Xiao Ma Jianan Zhang Hantian Liang Wei Zhang Hiroko Nakatsukasa Huiyuan Zhang Wenwen Jin Hong Jiang Jiyu Tong Xikun Zhou Ning Li Qi Zhang Hongbo Hu WanJun Chen Hao Xu Dunfang Zhang Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 Nature Communications |
| title | Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 |
| title_full | Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 |
| title_fullStr | Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 |
| title_full_unstemmed | Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 |
| title_short | Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2 |
| title_sort | regulatory t cell therapy promotes tgf β and il 6 dependent pro inflammatory th17 cell generation by reducing il 2 |
| url | https://doi.org/10.1038/s41467-025-62628-7 |
| work_keys_str_mv | AT haocheng regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT fangnan regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT ningji regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT xiaoma regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT jiananzhang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT hantianliang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT weizhang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT hirokonakatsukasa regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT huiyuanzhang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT wenwenjin regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT hongjiang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT jiyutong regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT xikunzhou regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT ningli regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT qizhang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT hongbohu regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT wanjunchen regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT haoxu regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 AT dunfangzhang regulatorytcelltherapypromotestgfbandil6dependentproinflammatoryth17cellgenerationbyreducingil2 |