Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2

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 () and Dunfang Zhang ()
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Hao Cheng: Sichuan University
Fang Nan: Sichuan University
Ning Ji: Sichuan University
Xiao Ma: Sichuan University
Jianan Zhang: Sichuan University
Hantian Liang: Sichuan University
Wei Zhang: Sichuan University
Hiroko Nakatsukasa: Graduate School of Pharmaceutical Sciences
Huiyuan Zhang: Sichuan University
Wenwen Jin: 30 Convent Drive
Hong Jiang: Sichuan University
Jiyu Tong: Sichuan University
Xikun Zhou: Sichuan University
Ning Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Qi Zhang: Zhejiang University School of Medicine
Hongbo Hu: Sichuan University
WanJun Chen: 30 Convent Drive
Hao Xu: Sichuan University
Dunfang Zhang: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62628-7

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