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

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 Huang and Hui Zhang ()
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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
Shuyi Wang: 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
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

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59786-z

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