Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 + FOXP3 + regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T regs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1 , which led to destabilization of forkhead box P3 (FOXP3) and T reg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T regs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T reg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T regs in autoimmune diseases.

中文翻译：

---

自身免疫转录回路驱动 FOXP3 + 调节性 T 细胞功能障碍


自身免疫性疾病是年轻人最常见的疾病之一，由遗传和环境因素介导。尽管 CD4 + FOXP3 + 调节性 T 细胞 (T regs ) 在预防自身免疫方面发挥着核心作用，但其功能障碍的分子机制尚不清楚。在这里，我们对自身免疫性疾病多发性硬化症 (MS) 中的 T reg 进行了全面的转录组和表观基因组分析，以确定调节人类自身免疫的关键转录程序。我们发现灵长类特异性 PR 结构域锌指蛋白 1 (PRDM1-S) 的短异构体的上调会诱导血清和糖皮质激素调节激酶 1 (SGK1) 的表达，独立于进化上保守的长 PRDM1 ，从而导致不稳定。叉头盒 P3 (FOXP3) 和 T reg 功能障碍。这种异常的 PRDM1-S/SGK1 轴在其他自身免疫性疾病中也存在。此外，多发性硬化症患者 T reg 的染色质景观分析显示，激活蛋白 1 (AP-1)/干扰素调节因子 (IRF) 转录因子结合丰富，是 PRDM1-S 表达和 T reg 功能障碍的候选上游调节因子。我们的研究揭示了一个机制模型，其中 PRDM1-S 的进化出现和 AP-1/IRF 的表观遗传启动可能是自身免疫性疾病中 T reg 功能障碍的关键驱动因素。