Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli 80131, Italy.
J Immunol. 2012 Sep 15;189(6):2941-53. doi: 10.4049/jimmunol.1200935. Epub 2012 Aug 17.
The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25-FOXP3- effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin-mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.
T 细胞对微环境中代谢和能量变化的感应可以决定这些细胞的分化、成熟和激活。虽然已知哺乳动物雷帕霉素靶蛋白（mTOR）可以衡量细胞外环境中的营养和能量信号，但目前尚不清楚 mTOR 和代谢如何影响 CD4+CD25-FOXP3-效应 T 细胞（Teff）的反应。在本文中，我们表明，瘦素诱导的 mTOR 激活，反过来又控制瘦素的产生和信号转导，导致了一个明确的细胞、生化和转录特征，决定了 Teff 反应的结果，无论是在体外还是体内。通过遗传手段或饥饿诱导的瘦素/瘦素受体信号阻断，导致 mTOR 活性受损，从而抑制体内 Teff 的增殖。值得注意的是，在瘦素阻断存在的情况下 Teff 的转录特征似乎与在 rapamycin 处理的 Teff 中观察到的相似。这些结果通过瘦素-mTOR 轴确定了营养状况与 Teff 反应之间的新联系，并定义了在正常和病理条件下调节 Teff 的潜在靶点。
