T cell receptor regulation of cytokine signaling

胸腺中的T细胞分化依赖于T细胞抗原受体和细胞因子受体的信号传导。我们目前对胸腺谱系选择是如何决定的理解是建立在T细胞抗原受体的信号传导阻止细胞因子受体的信号传导的概念之上的，细胞因子信号传导只有在T细胞抗原受体的信号传导停止后才会发生。尽管它在T细胞发育中起着核心作用，但目前尚不清楚T细胞抗原受体信号如何使细胞因子受体“脱敏”，从而使其不再能够将信号传递到细胞中。因此，我们对胸腺发育中的T细胞和周围成熟的T细胞中细胞因子受体信号被TCR信号破坏的分子基础进行了系统的研究。我们发现TCR信号上调靶向Janus激酶1 （Jak1）的microRNA mir-17的表达，Jak1的激活启动IL-7信号转导。出乎意料的是，我们发现Jak1是一种非常不稳定的蛋白，在T细胞中会迅速降解，因此需要持续的Jak1蛋白合成来维持Jak1在足够的水平以促进IL-7信号转导。因此，通过靶向Jak1 mRNA， mir-17抑制Jak1翻译和Jak1蛋白合成，从而严重破坏IL-7信号传导。

T cell differentiation in the thymus is dependent on signaling by both T cell antigen receptors and by cytokine receptors. Our current understanding of how lineage choice is determined in the thymus is built around the concept that signaling by the T cell antigen receptor prevents signaling by cytokine receptors, and that cytokine signaling only occurs after signaling by the T cell antigen receptor has ceased. Despite its central role in T cell development, it is not known how T cell antigen receptor signaling 'desensitizes' the cytokine receptor so that it is no longer able to transmit signals into the cell. Consequently, we have undertaken a systematic examination of the molecular basis by which cytokine receptor signaling is impaired by TCR signals in developing T cells in the thymus and in mature T cells in the periphery. We have discovered that TCR signals upregulate expression of the microRNA mir-17 that targets Janus kinase 1 (Jak1) whose activation initiates IL-7 signal transduction. Unexpectedly, we discovered that Jak1 is an extremely unstable protein which is rapidly degraded in T cells, so that continuous Jak1 protein synthesis is required to maintain Jak1 at levels sufficient to promote IL-7 signal transduction. Thus, by targeting Jak1 mRNA, mir-17 inhibits Jak1 translation and Jak1 protein synthesis, which acutely disrupts IL-7 signaling.