OBJECTIVE Takayasu arteritis (TAK) is a progressive autoimmune large vessel vasculitis with infiltration of proinflammatory T cells, with a largely unknown etiology. This study was undertaken to explore the involvement of mechanistic target of rapamycin (mTOR) in proinflammatory T cell differentiation and disease progression in TAK. METHODS Ninety-five patients with TAK, 26 patients with small vessel vasculitis, and 40 healthy donors were enrolled. Naive and memory CD4+ T cells were activated with anti-CD3/CD28 beads and analyzed for lineage differentiation. The mTORC1 activity was determined by quantifying intracellular phospho-S6 kinase 1 and phospho-S6 ribosomal protein. Rapamycin and lentiviral regulatory-associated protein of mTOR short hairpin RNA were used to block mTORC1 activity. Human artery-NSG mouse chimeras representing human TAK were established for targeting mTORC1 in disease treatment. RESULTS TAK CD4+ T cells were selectively prepositioned with hyperactivity of mTORC1 (P < 0.001), resulting in spontaneous maldifferentiation of Th1 and Th17 cells (P < 0.001). Activity of mTORC1high in circulating CD4+ T cells predicted elevated frequencies of proinflammatory T cells and active disease in TAK patients (P < 0.001). Blockade of mTORC1 with rapamycin efficiently abrogated the maldifferentiation of Th1 and Th17 cells (P < 0.01) and ameliorated vasculitis in humanized TAK chimeras (P < 0.001). Inhibition of mTORC1 using RNA interference technology is sufficient to reduce proinflammatory T cell frequencies (P < 0.01) and restrict TAK disease progression in vivo (P < 0.01). CONCLUSION Our findings indicate that hyperactivity of mTORC1 is a critical cell-intrinsic mechanism underlying spontaneous maldifferentiation of proinflammatory T cells in TAK patients. Targeting mTORC1 is a promising therapeutic strategy against TAK.

中文翻译：

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雷帕霉素复合物1的靶向机制靶标可限制促炎性T细胞分化并改善Takayasu动脉炎。

目的高隆动脉炎（TAK）是一种进行性自身免疫性大血管血管炎，伴有促炎性T细胞浸润，病因很多。进行这项研究以探讨雷帕霉素（mTOR）的机械靶标在TAK中促炎性T细胞分化和疾病进展中的作用。方法纳入95例TAK患者，26例小血管血管炎患者和40例健康供体。用抗CD3 / CD28珠激活幼稚和记忆CD4 + T细胞，并分析其谱系分化。通过定量细胞内磷酸S6激酶1和磷酸S6核糖体蛋白来确定mTORC1活性。雷帕霉素和mTOR短发夹RNA的慢病毒调节相关蛋白被用来阻断mTORC1的活性。建立了代表人类TAK的人类动脉NSG小鼠嵌合体，用于在疾病治疗中靶向mTORC1。结果TAK CD4 + T细胞被选择性地介导了mTORC1的过度活跃（P <0.001），导致Th1和Th17细胞自发性分化不良（P <0.001）。在TAK患者中，循环CD4 + T细胞中mTORC1high的活性预示着促炎性T细胞的频率升高和活动性疾病（P <0.001）。雷帕霉素对mTORC1的阻断有效消除了人源化TAK嵌合体中Th1和Th17细胞的分化不良（P <0.01）和血管炎的减轻（P <0.001）。使用RNA干扰技术抑制mTORC1足以降低促炎性T细胞频率（P <0.01）并限制体内TAK疾病的进展（P <0.01）。结论我们的研究结果表明mTORC1过度活跃是TAK患者促炎性T细胞自发性误分化的关键细胞内在机制。靶向mTORC1是针对TAK的有前途的治疗策略。