Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2
CD4<sup>+</sup>Foxp3<sup>+</sup> 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.
Authors
- Huiyuan Zhang (ORCID: https://orcid.org/0000-0002-1532-2462)
- Xikun Zhou (ORCID: https://orcid.org/0000-0001-6768-2382)
- WanJun Chen (ORCID: https://orcid.org/0000-0002-9335-2114)
- Hantian Liang
- Jiyu Tong (ORCID: https://orcid.org/0000-0002-5453-613X)
- Hao Xu (ORCID: https://orcid.org/0000-0002-5665-0139)
- Dunfang Zhang (ORCID: https://orcid.org/0000-0001-7545-9930)
- Hongbo Hu (ORCID: https://orcid.org/0000-0002-8177-7641)
- Wei Zhang (ORCID: https://orcid.org/0000-0003-0275-7376)
- Hiroko Nakatsukasa (ORCID: https://orcid.org/0000-0001-7023-9920)
- Jianan Zhang (ORCID: https://orcid.org/0000-0001-9801-2779)
- Ning Li (ORCID: https://orcid.org/0000-0002-7786-7986)
- Hong Jiang (ORCID: https://orcid.org/0000-0001-9481-9807)
- Qi Zhang (ORCID: https://orcid.org/0000-0002-6096-0690)
- Ning Ji (ORCID: https://orcid.org/0000-0001-6331-9148)
- Fang Nan (ORCID: https://orcid.org/0000-0002-9605-1413)
- Hao Cheng (ORCID: https://orcid.org/0000-0003-1282-3496)
- Wenwen Jin (ORCID: https://orcid.org/0000-0001-7771-3058)
- Xiao Ma (ORCID: https://orcid.org/0000-0002-2132-2469)
Institutions
- Chiba University (JP)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Sichuan University (CN)
- West China Medical Center of Sichuan University (CN)
- National Institute of Dental and Craniofacial Research (US)
- West China Second University Hospital of Sichuan University (CN)
- Sichuan Cancer Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-16
- DOI
- https://doi.org/10.1038/s41467-025-62628-7
- Citations
- 9
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 7.18
Funders
- National Natural Science Foundation of China
- Department of Science and Technology of Sichuan Province
- Sichuan University
- West China Hospital, Sichuan University