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TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis

Author

Listed:
  • Yimei Lai

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Shuang Wang

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Tingting Ren

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Jia Shi

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Yichao Qian

    (the First Affiliated Hospital of Sun Yat-sen University
    the First Affiliated Hospital of Sun Yat-sen University)

  • Shuyi Wang

    (the First Affiliated Hospital of Sun Yat-sen University
    the First Affiliated Hospital of Sun Yat-sen University)

  • Mianjing Zhou

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Ryu Watanabe

    (Osaka Metropolitan University Graduate School of Medicine)

  • Mengyuan Li

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Xinyuan Ruan

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Xin Wang

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Lili Zhuang

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Zunfu Ke

    (the First Affiliated Hospital of Sun Yat-sen University
    the First Affiliated Hospital of Sun Yat-Sen University
    the First Affiliated Hospital of Sun Yat-Sen University)

  • Niansheng Yang

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Yuefang Huang

    (the First Affiliated Hospital of Sun Yat-sen University)

  • Hui Zhang

    (the First Affiliated Hospital of Sun Yat-sen University
    the First Affiliated Hospital of Sun Yat-sen University)

Abstract

Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells’ differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases.

Suggested Citation

  • Yimei Lai & Shuang Wang & Tingting Ren & Jia Shi & Yichao Qian & Shuyi Wang & Mianjing Zhou & Ryu Watanabe & Mengyuan Li & Xinyuan Ruan & Xin Wang & Lili Zhuang & Zunfu Ke & Niansheng Yang & Yuefang H, 2025. "TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59786-z
    DOI: 10.1038/s41467-025-59786-z
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