Understanding T Cell Rapamycin Resistance

在这个项目中，我们发现在雷帕霉素存在下体外扩增的免疫T细胞可以产生对雷帕霉素的耐药性，只要提供必要的共刺激和细胞因子信号。重要的是，我们已经证明雷帕霉素可以产生多种功能性T细胞亚群，包括Th1、Th2、Tc1、Tc2和调节性T细胞亚群。重要的是，我们发现获得雷帕霉素抗性的T细胞也获得细胞凋亡抗性表型；这一生物学特性具有重要的功能意义，因为在过继T细胞转移后，这种抗雷帕霉素和抗凋亡的T细胞在体内存活增加，因此相对于对照T细胞介导更有效的免疫T细胞反应。我们最近发现，雷帕霉素导致极化的T细胞经历一个被称为自噬的过程；雷帕霉素产生的T细胞的抗凋亡表型依赖于自噬。我们已经观察到，这种生物学现象发生在小鼠T细胞和人类T细胞中。鉴于这一认识，我们已经在NIH临床中心启动了使用雷帕霉素耐药T细胞治疗白血病、淋巴瘤和肾细胞癌的试点临床试验。

In this project, we have found that immune T cells that are expanded ex vivo in the presence of rapamycin can develop resistance to rapamycin provided that necessary co-stimulation and cytokine signals are provided. Importantly, we have shown that a great variety of functional T cell subsets can be generated in rapamycin, including the Th1, Th2, Tc1, Tc2, and regulatory T cell subsets. Of significance, we have found that T cells that acquire rapamycin-resistance also attain an apoptosis resistance phenotype; this biology has functional significance because upon adoptive T cell transfer, such rapamycin- and apoptosis-resistant T cell have increased in vivo survival and therefore mediate more potent immune T cell reactions relative to control T cells. We have recently found that rapamycin causes polarized T cells to undergo a process known as autophagy; the anti-apoptotic phenotype of rapamycin-generated T cells is dependent upon autophagy. We have observed that this biology occurs with both murine T cells and human T cells. Given this understanding, we have initiated pilot clinical trials at the NIH Clinical Center using rapamycin-resistant T cells for the therapy of leukemia, lymphoma, and renal cell carcinoma.