The Role of Lymphoid Environments in Guiding T Cell Migration

淋巴环境在引导 T 细胞迁移中的作用

• 批准号: 7651227
• 负责人: ANDREW R. FERGUSON
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651227
• 关键词: Adhesions; Antigens; Bone Marrow; CD8B1 gene; Condition; Cytolysis; Data; Dendritic Cells; Environment; Generations; Growth; Homing; Immune response; Immunization; Infiltration; Location; Lymphoid; Mediating; Modeling; Mus; Proteins; Reporting; Role; Route; Site; T-Cell Activation; T-Cell Homing Receptors; T-Lymphocyte; Testing; Therapeutic; Tumor-Derived; cancer therapy; cell motility; chemokine receptor; melanoma; migration; neoplastic cell; pathogen; receptor; tumor

DESCRIPTION (provided by applicant): Immunization with dendritic cells (DCs) has exciting potential as a therapeutic for the treatment of cancer. DCs are attractive candidates due to their ability to stimulate naive T cells leading to T cell mediated tumor cell lysis. Murine bone marrow derived DCs (BMDCs) provide an important model to examine the immune response under controlled conditions limiting confounding issues such as immunomodulatory factors and antigen (Ag) persistence present in models of T cell activation by pathogens. The successful use of BMDCs as a therapeutic relies not only on the proper generation of T cells, but also their migration to diseased sites. The route of BMDC immunization dictates the site of T cell priming and recent data from this lab supports the importance of the site of T cell priming as the route of BMDC immunization influences the ability to protect against melanoma growth. While several reports have examined the role of adhesion proteins and chemokine receptors in guiding T cell migration, the role of these proteins in T cell migration in the context of a tumor is unknown. The studies in this proposal seek to evaluate the homing receptors on CD8 T cells that mediate tumor infiltration. In relation to this is how the site of CDS T cell activation by tumor-derived Ag presented by endogenous DCs and exogenous BMDCs influences the expression of homing receptors by CDS T cells. In addition, the expression of homing receptors on CDS T cells induced by BMDCs in the presence of a tumor will also be explored to understand any possible influence a tumor may have on BMDC induced T cell migration. These studies will test the hypothesis that BMDC immunization induces unique homing receptors on CDS T cells compared to activation by tumor-derived Ag presentation and altering the route of BMDC immunization to target different lymphoid compartments influences the ability of CDS T cells to infiltrate anatomically distinct tumors. The Specific Aims of this proposal are 1) To determine the CDS T cell homing receptor profile on activated CDS T cells that infiltrate tumors growing in distinct anatomical locations and examine the necessity of these homing receptors to mediate CDS T cell infiltration of anatomically distinct tumors. 2) To analyze the induction of homing receptors on CDS T cells activated by tumor-derived Ag presented by endogenous DCs in distinct lymphoid compartments and to determine how this compares to or is altered by exogenous immunization with BMDCs.

描述（由申请人提供）：使用树突状细胞（DC）进行免疫作为治疗癌症的疗法具有令人兴奋的潜力。 DC 是有吸引力的候选者，因为它们能够刺激初始 T 细胞，导致 T 细胞介导的肿瘤细胞裂解。鼠骨髓衍生的 DC (BMDC) 提供了一个重要的模型，用于在受控条件下检查免疫反应，限制了病原体激活 T 细胞模型中存在的免疫调节因子和抗原 (Ag) 持久性等混杂问题。 BMDC 作为治疗药物的成功使用不仅依赖于 T 细胞的正确生成，还依赖于它们向患病部位的迁移。 BMDC 免疫途径决定了 T 细胞启动位点，该实验室的最新数据支持 T 细胞启动位点的重要性，因为 BMDC 免疫途径影响防止黑色素瘤生长的能力。虽然一些报告已经研究了粘附蛋白和趋化因子受体在引导 T 细胞迁移中的作用，但这些蛋白在肿瘤背景下 T 细胞迁移中的作用尚不清楚。该提案中的研究旨在评估 CD8 T 细胞上介导肿瘤浸润的归巢受体。与此相关的是内源性 DC 和外源 BMDC 呈递的肿瘤源性 Ag 激活 CDS T 细胞的位点如何影响 CDS T 细胞归巢受体的表达。此外，还将探索肿瘤存在下 BMDC 诱导的 CDS T 细胞上归巢受体的表达，以了解肿瘤可能对 BMDC 诱导的 T 细胞迁移产生的任何影响。这些研究将检验以下假设：与肿瘤源性 Ag 呈递激活相比，BMDC 免疫会诱导 CDS T 细胞上独特的归巢受体，并且改变 BMDC 免疫途径以靶向不同的淋巴区会影响 CDS T 细胞浸润解剖学上不同的肿瘤的能力。该提案的具体目标是 1) 确定浸润在不同解剖位置生长的肿瘤的激活 CDS T 细胞上的 CDS T 细胞归巢受体谱，并检查这些归巢受体介导解剖学上不同肿瘤的 CDS T 细胞浸润的必要性。 2) 分析由不同淋巴区中的内源性 DC 呈递的肿瘤源性 Ag 激活的 CDS T 细胞上归巢受体的诱导，并确定其与 BMDC 的外源免疫相比或如何改变。