Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)–mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3⁺ regulatory T cell (T_reg) induction in vitro. Accordingly, T_reg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect T_reg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)–mediated NFAT5, which interferes with FoxP3⁺ T_reg induction. Blocking miRNA181a or NFAT5 increases T_reg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.

尚未完全了解触发胰岛自身免疫或进展为人类1型糖尿病（T1D）的分子检查点。使用来自没有临床T1D的胰岛自身免疫早期儿童的T细胞，我们发现microRNA181a（miRNA181a）介导的刺激信号强度增强和共刺激将激活的T细胞5（NFAT5）的核因子与耐受性诱导和抑制联系在一起。自身免疫激活。我们显示增强miRNA181a活性增加NFAT5表达，同时在体外抑制FOXP3 ⁺调节性T细胞（T _reg）诱导。因此，使用来自NFAT5基因敲除（NFAT5ko）动物的T细胞可改善T _reg诱导，而改变miRNA181a活性不会影响T _regNFAT5ko T细胞中被诱导。此外，高共刺激信号导致磷酸肌醇3激酶（PI3K）介导的NFAT5干扰FoxP3 ⁺ T _reg的诱导。阻断miRNA181a或NFAT5可以在鼠类和人源化模型中增加T _reg诱导，并在体内降低鼠类胰岛自身免疫性。这些发现表明，针对miRNA181a和/或NFAT5信号传导的目标是开发创新的个性化药物以限制胰岛自身免疫。