CXCR4 Chemokine Receptor Regulation of ERK MAP Kinase

CXCR4 趋化因子受体对 ERK MAP 激酶的调节

• 批准号: 8813582
• 负责人: KAREN E. HEDIN
• 金额: $ 31.01万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813582
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animals; Antigen Receptors; Autoimmune Diseases; Autoimmunity; Binding; Biological; CXCR4 gene; Cell physiology; Cells; Chemicals; Complex; Coupled; Data; Development; Disease; Extracellular Signal Regulated Kinases; Functional disorder; Funding; GTP-Binding Proteins; Gene Expression; Grant; HIV-1; Human; ITAM; Immune; Immune Tolerance; Immune response; Immune system; Immunity; In Vitro; Inflammatory Bowel Diseases; Interleukin-10; Knowledge; LCP2 gene; Life; Ligands; Ligation; Location; Lymphocyte antigen; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Mus; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphatidylinositols; Phospholipase; Phospholipase C; Phosphorylation; Physiological; Play; Protein Isoforms; Receptor-CD3 Complex, Antigen, T-Cell; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stromal Cell-Derived Factor 1; Structure; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Tissues; Virus Diseases; Work; ZAP-70 Gene; autoimmune inflammatory bowel disease; cell motility; chemokine receptor; experience; immune activation; immune function; in vivo; inhibitor/antagonist; lymph nodes; migration; mouse model; novel; prevent; promoter; response

DESCRIPTION (provided by applicant): Extensive cross-regulation of immune function has been reported between the T lymphocyte antigen receptor (TCR) that mediates T cell immune activation, and CXCR4, a chemokine receptor that stimulates cell migration and gene expression. Yet the molecular mechanisms responsible for the integration of CXCR4 and TCR signal transduction pathways are still mostly unknown. The CXCR4 ligand, SDF-1, is constitutively expressed in many tissues, including lymph nodes and gut. CXCR4 is widely expressed and critically regulates multiple diseases, including HIV-1/AIDS and cancer. At the beginning of the last funding cycle, we showed that SDF-1 signals in T cells by inducing the formation of CXCR4-TCR heterodimeric complexes, which are required for SDF-1 to stimulate migration, increase cytosolic Ca2+, and activate the ERK MAP kinase pathway and gene expression. During the last cycle of this grant, we found that CXCR4-TCR complexes signal in regulatory T cells (Tregs) to potently increase IL-10 secretion via a signaling pathway that specifically requires a particular phospholipase isoform, PLC-23. We also found that CXCR4-TCR signaling via PLC-23 critically cross- regulates and antagonizes naive T cell activation in response to ligation of the TCR, even in the absence of SDF-1. IL-10 is an immune modulator and inhibitor of T cell-mediated autoimmunity including inflammatory bowel disease (IBD). Thus, our results indicate that CXCR4-TCR signaling via PLC-23 is a potent promoter of immune tolerance that both enhances functions of Tregs while modulating activation of naive T cells. Assessing the physiological significance of these observations is important, however, until now this has been difficult since targeting either CXCR4 or the TCR disrupts multiple immune functions including T cell development and homeostatic T cell migration patterns. Since PLC-23 is required for many immune effects of CXCR4-TCR complexes but not for T cell migration, we here propose to address the molecular mechanisms and in vivo immune impact of CXCR4-TCR signaling via PLC-23 by studying PLC-23-/- mice. Our Central Hypothesis is that signaling by the CXCR4-TCR heterodimer depends on PLC-23 in order to activate the Ras- ERK pathway to promote Treg functions, and to antagonize TCR signaling, thereby inhibiting autoimmunity. Our Specific Aims are to: 1) Characterize the molecular mechanisms by which the CXCR4-TCR heterodimer uses PLC-23 for signaling, 2) Determine the role of CXCR4-TCR heterodimer signaling via PLC-23 in regulating Tregs and preventing autoimmune disease in vivo, and 3) Characterize the role of the CXCR4-TCR heterodimer and PLC-23 in modulating TCR signaling and T cell immune responses in vivo. Together, the proposed studies will address key questions regarding the in vivo immune impact of CXCR4-TCR heterodimers and PLC-23. These studies also have the potential to characterize PLC-23 as a novel pharmacologic target that could be used to selectively enhance CXCR4-TCR heterodimer signaling and thereby Treg function and tolerance without disrupting the normal in vivo migration patterns of immune cells.

描述（由申请人提供）：据报道，介导 T 细胞免疫激活的 T 淋巴细胞抗原受体 (TCR) 和刺激细胞迁移和基因表达的趋化因子受体 CXCR4 之间存在广泛的免疫功能交叉调节。然而，负责 CXCR4 和 TCR 信号转导途径整合的分子机制仍然大多未知。 CXCR4 配体 SDF-1 在许多组织中组成型表达，包括淋巴结和肠道。 CXCR4 广泛表达并严格调节多种疾病，包括 HIV-1/AIDS 和癌症。在上一个资助周期开始时，我们发现 SDF-1 通过诱导 CXCR4-TCR 异二聚体复合物的形成在 T 细胞中发出信号，这是 SDF-1 刺激迁移、增加胞质 Ca2+ 并激活 ERK MAP 激酶途径和基因表达所必需的。在本次资助的最后一个周期中，我们发现 CXCR4-TCR 复合物在调节性 T 细胞 (Treg) 中发出信号，通过专门需要特定磷脂酶异构体 PLC-23 的信号通路有效增加 IL-10 的分泌。我们还发现，即使在不存在 SDF-1 的情况下，通过 PLC-23 的 CXCR4-TCR 信号传导也会对 TCR 连接反应中的初始 T 细胞激活进行关键的交叉调节和拮抗。 IL-10 是一种免疫调节剂和 T 细胞介导的自身免疫抑制剂，包括炎症性肠病 (IBD)。因此，我们的结果表明，通过 PLC-23 的 CXCR4-TCR 信号传导是免疫耐受的有效促进剂，既增强 Tregs 的功能，同时调节初始 T 细胞的激活。评估这些观察结果的生理意义很重要，然而，到目前为止，这一直很困难，因为靶向 CXCR4 或 TCR 会破坏多种免疫功能，包括 T 细胞发育和稳态 T 细胞迁移模式。由于 CXCR4-TCR 复合物的许多免疫作用需要 PLC-23，但 T 细胞迁移不需要 PLC-23，因此我们在此建议通过研究 PLC-23-/- 小鼠来解决 CXCR4-TCR 信号传导通过 PLC-23 的分子机制和体内免疫影响。我们的中心假设是CXCR4-TCR异二聚体的信号传导依赖于PLC-23来激活Ras-ERK通路以促进Treg功能，并拮抗TCR信号传导，从而抑制自身免疫。我们的具体目标是：1) 表征 CXCR4-TCR 异二聚体使用 PLC-23 进行信号传导的分子机制，2) 确定 CXCR4-TCR 异二聚体通过 PLC-23 信号传导在调节 Tregs 和预防体内自身免疫性疾病中的作用，以及 3) 表征 CXCR4-TCR 异二聚体和 PLC-23 在调节 TCR 中的作用 体内信号传导和 T 细胞免疫反应。总之，拟议的研究将解决有关 CXCR4-TCR 异二聚体和 PLC-23 体内免疫影响的关键问题。这些研究还有可能将 PLC-23 描述为一种新型药理学靶点，可用于选择性增强 CXCR4-TCR 异二聚体信号传导，从而增强 Treg 功能和耐受性，而不破坏免疫细胞正常的体内迁移模式。