CXCR4 Chemokine Receptor regulation of ERK MAP Kinase

描述（由申请方提供）：T淋巴细胞活化和迁移对于正常免疫功能至关重要，T淋巴细胞抗原受体-CD 3复合物（TCR）和趋化因子受体（如CXCR 4）的信号传导受到广泛交叉调节。 例如，CXCR 4共刺激TCR刺激的T淋巴细胞的免疫活化，而TCR信号传导消除CXCR 4介导的迁移并参与CXCR 4介导的T淋巴细胞感染人类免疫缺陷病毒-1（HIV-1）。 尽管有证据表明TCR和CXCR 4信号通路以重要方式交叉调节，但T淋巴细胞中的CXCR 4信号通路的特征并不完全。 此外，据我们所知，还没有关于趋化因子或CXCR 4与TCR交叉调节的分子机制的详细研究报道。 我们最近的研究结果表明，CXCR 4信号调节CXCR 4和T淋巴细胞表面TCR之间的密切联系，并通过需要TCR和TCR相关信号分子的机制激活ERK MAP激酶。 因此，我们提出的实验将填补目前知识中的这一空白，通过测试中心假设，即CXCR 4通过一种新的机制在T细胞中发出信号，该机制涉及CXCR 4与TCR结合并使用TCR进行信号转导。 我们的具体目标是（1）询问CXCR 4和TCR之间的相互作用是否是特异性的，（2）询问CXCR 4信号传导如何调节CXCR 4/TCR复合物及其进入信号传导发生的亚细胞区室的运动，以及（3）询问CXCR 4是否使用TCR和其他信号蛋白激活ERK和共刺激TCR信号传导。这些研究的结果将表征T细胞中CXCR 4信号传导的新机制，这些机制对CXCA 4介导的基因表达很重要，并且可能也有助于CXCR 4介导的T细胞活化和HIV-1病理学的共刺激。 此外，无论CXCR 4/TCR复合物最终是否被发现具有生物学相关性，这些实验将解决受体如何寡聚化和亚细胞区室内信号的基本问题。 最后，这些实验将确定可用于严格测试CXCR 4/TCR复合物调节T淋巴细胞生物学功能的想法的试剂。因此，这些研究的结果将作为更好地理解和操纵T细胞免疫激活和T细胞迁移之间相互作用的理论框架。

DESCRIPTION (provided by the applicant): T lymphocyte activation and migration are critical for normal immune functions, and signaling by the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross regulated. For example, CXCR4 costimulates the immune activation of TCR-stimulated T lymphocytes, while TCR signaling abrogates CXCR4-mediated migration and participates in CXCR4-mediated infection of T lymphocytes with the Human Immunodeficiency Virus-1 (HIV-1). Despite evidence that TCR and CXCR4 signaling pathways cross-regulate in important ways, CXCR4 signaling pathways in T lymphocytes are incompletely characterized. Moreover, to our knowledge, no detailed studies on the molecular mechanisms of chemokine or CXCR4 and TCR cross-regulation have been reported. Our recent results demonstrate that CXCR4 signaling regulates a close association between CXCR4 and TCR on the surface of T lymphocytes, and activates the ERK MAP kinase via a mechanism requiring the TCR and TCR associated signaling molecules. Our proposed experiments will therefore fill this gap in the current knowledge, by testing the central hypothesis that CXCR4 signals in T cells via a novel mechanism that involves CXCR4 associating with the TCR and using the TCR for signal transduction. Our specific aims are to (1) ask if the interaction between CXCR4 and the TCR is specific, (2) ask how CXCR4 signaling regulates the CXCR4/TCR complex and its movement into subcellular compartments where signaling takes place, and (3) ask if CXCR4 uses the TCR and other signaling proteins for ERK activation and costimulation of TCR signaling. The results of these studies will characterize novel mechanisms of CXCR4 signaling in T cells that are important for CXCA4-mediated gene expression, and that probably also contribute to CXCR4-mediated costimulation of T cell activation and HIV-1 pathobiology. In addition, whether or not the CXCR4/TCR complex is eventually found to have biological relevance, these experiments will address basic questions of how receptors oligomerize, and signal from within, subcellular compartments. Finally, these experiments will identify reagents that can be used to rigorously test the idea that CXCR4/TCR complexes regulate T lymphocyte biological functions. The results of these studies will therefore serve as a theoretical framework for better understanding and manipulating the interplay between T cell immune activation and T cell migration.