CXCR4 Chemokine Receptor Regulation of ERK MAP Kinase

描述（申请人提供）：T淋巴细胞的激活和迁移是正常免疫功能的关键。T淋巴细胞抗原受体- cd3复合物（TCR）和趋化因子受体（如CXCR4）的信号传导被广泛交叉调节，然而，直到最近，人们对这种交叉调节的分子机制知之甚少。此外，尽管CXCR4是普遍表达的，高度保守的，并且是人类免疫缺陷病毒-1 （HIV-1）感染T细胞所必需的，但很少有人提出T淋巴细胞CXCR4的特异性免疫功能。CXCR4配体SDF-1在特定解剖部位组成性表达，包括骨髓、淋巴结和肠道。因此，T细胞上的SDF-1/CXCR4信号可能在这些位置关键地调节T细胞免疫激活。我们的研究结果表明，SDF-1刺激CXCR4通过一种新的机制在T细胞中产生信号：通过诱导CXCR4/TCR复合物的形成，然后利用TCR ITAM结构域和TCR相关信号分子激活Ras/ERK MAP激酶途径。我们的初步结果进一步表明，该途径动员ap -1依赖的转录因子，这些转录因子负责SDF-1共同刺激T细胞产生和分泌IL-10。下面提出的实验旨在进一步表征这种新型信号通路的三个关键领域。目标1和目标2将检验SDF-1刺激的中心假设。CXCR4/TCR复合物的形成是通过增强CXCR4转运到含有组成性再循环TCR分子的晚期再循环核内体中，并且这些囊泡在MTOC和高尔基体附近的聚集允许CXCR4/TCR复合物通过核内体和/或高尔基体上的Ras-ERK途径组分发出信号。目的3将验证该信号通路增强T细胞分泌IL-10从而关键调节免疫的相关假设。总之，这些研究的结果将描述最近发现的CXCR4信号在T细胞中的新机制的关键点，该机制也可能参与CXCR4介导的迁移、整合素调控和HIV-1病理生物学。此外，所提出的研究结果将描述该途径对CXCR4共同刺激T细胞IL-10分泌和免疫调节的重要性，这些结果有可能改善依赖IL-10的人类自身免疫性疾病的治疗。

DESCRIPTION (provided by applicant): T lymphocyte activation and migration are critical for normal immune functions. Signaling by both the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross-regulated, however, until recently little was known about the molecular mechanisms responsible for this cross-regulation. Moreover, although CXCR4 is ubiquitously-expressed, highly conserved, and essential for Human Immunodeficiency Virus-1 (HIV-1) infection of T cells, few specific immune function(s) of T lymphocyte CXCR4 have been proposed. The CXCR4 ligand, SDF-1, is constitutively expressed at specific anatomic sites, include the bone marrow, lymph nodes, and gut. SDF-1/CXCR4 signaling on T cells may, therefore, critically modulate T cell immune activation in these locations. Our results during the last cycle of this grant (recently published in Immunity) indicate that SDF-1 stimulation of CXCR4 produces signals in T cells via a novel mechanism: by inducing the formation of CXCR4/TCR complexes which then utilize the TCR ITAM domains and TCR-associated signaling molecules to activate the Ras/ERK MAP kinase pathway. Our preliminary results further indicate that this pathway mobilizes AP-1-dependent transcription factors that are responsible for SDF-1 co-stimulation of IL-10 production and secretion by T cells. Experiments proposed below are designed to further characterize three key areas of this novel signaling pathway. Aims 1 & 2 will test the central hypothesis that SDF-1 stimulates .the formation of CXCR4/TCR complexes by enhancing the trafficking of CXCR4 into late recycling endosomes that also contain constitutively-recycling TCR molecules, and that the clumping of these vesicles near the MTOC and Golgi permits CXCR4/TCR complexes to signal via Ras-ERK pathway components on the endosomes and/or Golgi. Aim 3 will test the related hypothesis that this signaling pathway enhances T cell secretion of IL-10 and thereby critically modulates immunity. Together, the results of the proposed studies will characterize key points of the recently-discovered novel mechanism by which CXCR4 signals in T cells, and that may also participate in CXCR4-mediated migration, integrin regulation and HIV-1 pathobiology. In addition, the results of the proposed studies will delineate the importance of this pathway for CXCR4 co-stimulation of T cell IL-10 secretion and immune regulation, results that have the potential improve therapies of human autoimmune diseases that depend on IL-10.