Background T helper cells in patients with autoimmune disease of idiopathic inflammatory myopathies (IIM) are characterized with the proinflammatory phenotypes. The underlying mechanisms remain unknown. Methods RNA sequencing was performed for differential expression genes. Gene expression in CD4 + T‐cells was confirmed by quantitative real‐time PCR. CD4 + T‐cells from IIM patients or healthy controls were evaluated for metabolic activities by Seahorse assay. Glucose uptake, T‐cell proliferation and differentiation were evaluated and measured by flow cytometry. Human CD4 + T‐cells treated with iron chelators or Pfkfb4 siRNA were measured for glucose metabolism, proliferation and differentiation. Signalling pathway activation was evaluated by western blot and flow cytometry. Mouse model of experimental autoimmune myositis (EAM) were induced and treated with iron chelator or rapamycin. CD4 + T‐cell differentiation and muscle inflammation in the EAM mice were evaluated. Results RNA‐sequencing analysis revealed that iron was involved with glucose metabolism and CD4 + T‐cell differentiation. IIM patient‐derived CD4 + T‐cells showed enhanced glycolysis and mitochondrial respiration, which was inhibited by iron chelation. CD4 + T‐cells from patients with IIM was proinflammatory and iron chelation suppressed the differentiation of interferon gamma (IFNγ)‐ and interleukin (IL)‐17A‐producing CD4 + T‐cells, which resulted in an increased percentage of regulatory T (Treg) cells. Mechanistically, iron promoted glucose metabolism by an upregulation of PFKFB4 through AKT‐mTOR signalling pathway. Notably, the knockdown of Pfkfb4 decreased glucose influx and thus suppressed the differentiation of IFNγ‐ and IL‐17A‐producing CD4 + T‐cells. In vivo, iron chelation inhibited mTOR signalling pathway and reduced PFKFB4 expression in CD4 + T‐cells, resulting in reduced proinflammatory IFNγ‐ and IL‐17A‐producing CD4 + T‐cells and increased Foxp3 + Treg cells, leading to ameliorated muscle inflammation. Conclusions Iron directs CD4 + T‐cells into a proinflammatory phenotype by enhancing glucose metabolism. Therapeutic targeting of iron metabolism should have the potential to normalize glucose metabolism in CD4 + T‐cells and reverse their proinflammatory phenotype in IIM.

Tissue-resident memory T cells (TRM cells) have been shown to play an instrumental role in providing local immune responses for pathogen clearance in barrier tissues. However, their contribution to inflammatory bowel diseases (IBDs) and the underlying regulation are less clear. Here, we identified a critical role of T-cell immunoreceptor with immunoglobulin and ITIM (TIGIT) in regulating CD4+ TRM cells in an experimental model of intestinal inflammation. We found that CD4+ TRM cells were increased and correlated with disease activities in mice with dextran sulfate sodium (DSS)-induced colitis. Phenotypically, these CD4+ TRM cells could be classified into CD69+CD103− and CD69+CD103+ subsets. Functionally, these CD4+ TRM cells were heterogeneous. CD69+CD103− CD4+ TRM cells were pro-inflammatory and produced interferon-γ (IFNγ) and interleukin-17A (IL-17A), which accounted for 68.7% and 62.9% of total IFNγ+ and IL-17A+ CD4+ T cells, respectively, whereas CD69+CD103+ CD4+ TRM cells accounted for 73.7% Foxp3+ regulatory T cells. TIGIT expression was increased in CD4+ T cells in the gut of mice with DSS-induced colitis. TIGIT deficiency impaired IL-17A expression in CD69+CD103− CD4+ TRM cells specifically, resulting in ameliorated gut inflammation and tissue injury. Together, this study provides new insights into the regulation of gut inflammation that TIGIT deficiency protects mice from DSS-induced colitis, which might have a potential therapeutic value in the treatment of IBDs.