T cell receptor regulation of cytokine signaling

T 细胞受体对细胞因子信号传导的调节

• 批准号: 10702478
• 负责人: Alfred Singer
• 金额: $ 38.68万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702478
• 关键词: Acute; Cells; Cytokine Receptors; Cytokine Signaling; Development; Goals; IL7 Signaling Pathway; IL7 gene; Impairment; JAK1 gene; Malignant Neoplasms; Mature T-Lymphocyte; Messenger RNA; MicroRNAs; Molecular; Protein Biosynthesis; Proteins; Receptor Cross-Talk; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; T cell differentiation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Therapeutic; Thymus Gland; Translations; desensitization; prevent

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.

胸腺中的T细胞分化依赖于T细胞抗原和T细胞免疫应答的信号传导。 受体和细胞因子受体。我们目前对血统选择的理解 在胸腺中确定的是建立在T细胞抗原的信号传导的概念上的， 受体阻止细胞因子受体的信号传导，细胞因子信号传导只发生在 在T细胞抗原受体的信号传导停止后。尽管它在T细胞中起着重要作用， 在发育过程中，尚不清楚T细胞抗原受体信号传导如何使细胞因子“脱敏”。 受体，使其不再能够将信号传递到细胞中。因此，我们有 对细胞因子受体的分子基础进行了系统的研究， 在胸腺中发育的T细胞和成熟的T细胞中，TCR信号损害了信号传导 在外围。我们已经发现TCR信号上调microRNA的表达， 靶向Janus激酶1（Jak 1）的mir-17，Janus激酶1的激活启动IL-7信号转导。 出乎意料的是，我们发现Jak 1是一种非常不稳定的蛋白质， 在T细胞中降解，因此需要持续的Jak 1蛋白合成来维持Jak 1在 足以促进IL-7信号转导的水平。因此，通过靶向Jak 1 mRNA，mir-17 抑制Jak 1翻译和Jak 1蛋白合成，从而严重破坏IL-7 发信号。