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, Dunfang Zhang
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. Regulatory T cell therapy has shown some success therapeutically in the context of autoimmunity and transplantation. Here the authors explore the impact of IL-6, TGF-β and IL-2 on pathogenic Th17 cell generation post regulatory T cell therapy, and show therapeutic blockade of IL-6/STAT3 can reduce their generation in murine models of inflammatory disease.