2. Academic Validation
  3. TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolic‒epigenetic mechanism in autoimmune myositis

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

  • Nat Commun. 2025 May 15;16(1):4502. doi: 10.1038/s41467-025-59786-z.
Yimei Lai # 1,  Shuang Wang # 1,  Tingting Ren # 1,  Jia Shi 1,  Yichao Qian 1 2,  Shuyi Wang 1 2,  Mianjing Zhou 1,  Ryu Watanabe 3,  Mengyuan Li 1,  Xinyuan Ruan 1,  Xin Wang 4,  Lili Zhuang 1,  Zunfu Ke 2 5 6,  Niansheng Yang 1,  Yuefang Huang 4,  Hui Zhang 7 8
Affiliations

Affiliations

  • 1 Department of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
  • 4 Department of Pediatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Pathology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 6 Molecular Diagnosis and Gene Test Centre, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 7 Department of Rheumatology and Clinical immunology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. zhangh656@mail.sysu.edu.cn.
  • 8 Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. zhangh656@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40374622 DOI: 10.1038/s41467-025-59786-z
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.

Figures
Products