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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月16日

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  • 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

摘要

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.