Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Blood. 2013 May 2;121(18):3619-30. doi: 10.1182/blood-2012-08-448290. Epub 2013 Feb 26.
Mammalian target of rapamycin (mTOR) is an important, yet poorly understood integrative kinase that regulates immune cell function. mTOR functions in 2 independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant rapamycin (RAPA) inhibits mTORC1 but not mTORC2 and causes a paradoxical reduction in anti-inflammatory interleukin (IL) 10 and B7-homolog 1 (B7-H1) expression by dendritic cells (DCs). Using catalytic mTOR inhibitors and DCs lacking mTORC2, we show that restraint of signal transducer and activator of transcription 3-mediated IL-10 and B7-H1 expression during DC maturation involves a RAPA-insensitive and mTORC2-independent mTOR mechanism. Relatedly, catalytic mTOR inhibition promotes B7-H1-dependent and IL-1β-dependent DC induction of regulatory T cells (Tregs). Thus, we define an immunoregulatory pathway in which RAPA-sensitive mTORC1 in DCs promotes effector T-cell expansion and RAPA-insensitive mTORC1 restrains T(reg) induction. These findings identify the first known RAPA-insensitive mTOR pathway that is not mediated solely by mTORC2 and have implications for the use of catalytic mTOR inhibitors in inflammatory disease settings.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种重要但尚未完全了解的整合激酶，可调节免疫细胞功能。mTOR 在 2 个独立的复合物中发挥作用：mTOR 复合物（mTORC）1 和 2。免疫抑制剂雷帕霉素（RAPA）抑制 mTORC1 但不抑制 mTORC2，并导致树突状细胞（DC）中抗炎性白细胞介素（IL）10 和 B7 同源物 1（B7-H1）表达的悖论性降低。使用催化 mTOR 抑制剂和缺乏 mTORC2 的 DC，我们表明，在 DC 成熟过程中，转录激活因子 3 介导的 IL-10 和 B7-H1 表达的抑制涉及一种 RAPA 不敏感和 mTORC2 独立的 mTOR 机制。相关地，催化 mTOR 抑制促进 B7-H1 依赖性和 IL-1β依赖性 DC 诱导调节性 T 细胞（Tregs）。因此，我们定义了一个免疫调节途径，其中 DC 中的 RAPA 敏感 mTORC1 促进效应 T 细胞的扩增，而 RAPA 不敏感 mTORC1 抑制 Treg 的诱导。这些发现确定了第一个已知的 RAPA 不敏感的 mTOR 途径，该途径不仅仅由 mTORC2 介导，并对在炎症性疾病环境中使用催化 mTOR 抑制剂具有重要意义。
