The Role of Lymphoid Environments in Guiding T Cell Migration

描述（由申请人提供）：树突状细胞免疫作为一种治疗癌症的疗法具有令人兴奋的潜力。树突状细胞是有吸引力的候选者，因为它们能够刺激幼稚T细胞导致T细胞介导的肿瘤细胞裂解。小鼠骨髓来源的dc （bmdc）提供了一个重要的模型来研究受控条件下的免疫反应，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）持久性等混淆问题。BMDCs作为一种治疗方法的成功使用不仅依赖于T细胞的适当产生，而且依赖于它们向患病部位的迁移。BMDC免疫途径决定了T细胞启动的位置，该实验室最近的数据支持T细胞启动位置的重要性，因为BMDC免疫途径影响抗黑色素瘤生长的能力。虽然有几篇报道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。本研究旨在评估介导肿瘤浸润的CD8 T细胞上的归巢受体。与此相关的是，由内源性dc和外源性BMDCs呈现的肿瘤源性Ag激活CDS T细胞的位置如何影响CDS T细胞的归巢受体表达。此外，在肿瘤存在的情况下，BMDC诱导的CDS T细胞上归巢受体的表达也将被探索，以了解肿瘤可能对BMDC诱导的T细胞迁移的任何可能影响。这些研究将验证与肿瘤源性银呈递激活相比，BMDC免疫在CDS T细胞上诱导独特的归巢受体的假设，以及改变BMDC免疫途径以靶向不同淋巴细胞室影响CDS T细胞浸润解剖上不同肿瘤的能力。本提案的具体目的是：1)确定浸润生长在不同解剖位置的肿瘤的活化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CDS T细胞浸润解剖位置不同的肿瘤的必要性。2)分析由不同淋巴室内源性dc呈递的肿瘤源性Ag激活的CDS T细胞对归巢受体的诱导作用，并确定其与BMDCs外源性免疫的比较或改变。

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.