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<p>Multiple sclerosis (MS) is a neurodegenerative autoimmune disease primarily mediated by T helper 17 (T<sub>H</sub>17) cells. We previously showed that Itch/WWP2 double knockout (DKO) T cells produce high levels of type 2 cytokines, driving spontaneous autoinflammation. Here, we report that DKO T<sub>H</sub>2-high carrying autoantigen-specific TCR (2D2) develop atypical spontaneous experimental autoimmune encephalomyelitis (EAE), with CD4<sup>+</sup> T cells simultaneously producing IL-4 and GM-CSF, directly causing neuroinflammation. Unexpectedly, IL-4 deletion in DKO T<sub>H</sub>2-high 2D2 mice exacerbates T<sub>H</sub>17-driven classical EAE, indicating a T<sub>H</sub>2 to T<sub>H</sub>17 conversion. Furthermore, we show that the JAK3/STAT5 signaling pathway is critical for maintaining T<sub>H</sub>2 lineage stability by modulating Blimp1 and c-Maf thereby suppressing T<sub>H</sub>17 differentiation. Importantly, we find that this phenomenon can also be observed in dupilumab-treated patients with atopic dermatitis who develop psoriasis. Thus, our findings uncover the molecular antagonism and plasticity in the T<sub>H</sub>2 and T<sub>H</sub>17 cell programs and identify potential therapeutic targets for modulating T<sub>H</sub>2 and T<sub>H</sub>17 cell responses in autoimmune diseases.</p>

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The E3 ligases Itch and WWP2 regulate autoimmune neuroinflammation by controlling TH2 to TH17 cell conversion via interleukin-4-STAT5 axis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月23日

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  • Mei Zhao,
  • Chao Zhang,
  • Xin Zhang,
  • Qingdian Mu,
  • Qian Li,
  • Yun-Cai Liu

摘要

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease primarily mediated by T helper 17 (TH17) cells. We previously showed that Itch/WWP2 double knockout (DKO) T cells produce high levels of type 2 cytokines, driving spontaneous autoinflammation. Here, we report that DKO TH2-high carrying autoantigen-specific TCR (2D2) develop atypical spontaneous experimental autoimmune encephalomyelitis (EAE), with CD4+ T cells simultaneously producing IL-4 and GM-CSF, directly causing neuroinflammation. Unexpectedly, IL-4 deletion in DKO TH2-high 2D2 mice exacerbates TH17-driven classical EAE, indicating a TH2 to TH17 conversion. Furthermore, we show that the JAK3/STAT5 signaling pathway is critical for maintaining TH2 lineage stability by modulating Blimp1 and c-Maf thereby suppressing TH17 differentiation. Importantly, we find that this phenomenon can also be observed in dupilumab-treated patients with atopic dermatitis who develop psoriasis. Thus, our findings uncover the molecular antagonism and plasticity in the TH2 and TH17 cell programs and identify potential therapeutic targets for modulating TH2 and TH17 cell responses in autoimmune diseases.