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, Hui Zhang
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. Aberrant activation of autoreactive T cells is a hallmark of autoimmune diseases. Here, by analysing CD4 T cells from patients with polymyositis and mice with experimental autoimmune myositis, the authors show that TIGIT limits the differentiation of inflammatory Th1 and Th17 cells via a metabolic-epigenetic mechanism, which involves the inhibition of CD28-mediated PI3K/AKT/mTOR costimulatory signaling.