Regulation of effector T cell migration within inflamed tissues

描述（由申请人提供）：免疫介导的保护的基础是白细胞调查屏障表面并快速响应感染或组织损伤的能力。来自组织内的细胞因子、趋化因子和细胞（免疫和基质）的信号为炎症部位的T细胞迁移提供了关键线索，但对这些信号的T细胞运动机制知之甚少。我们的总体目标是确定功能不同的炎症部位内T细胞监测的机制控制点。在长期鉴定T细胞功能的不同需求将导致特定组织或病理的选择性治疗靶向。炎症导致组织结构及其组成的变化。利用活体多光子显微镜观察炎症组织，我们发现炎症皮肤中的间质T细胞运动高度依赖于α-v整合素。α-v的阻断或基因敲低使T细胞间质运动停止，并且还减弱效应子功能。我们假设T细胞-基质相互作用对于淋巴细胞监视炎症组织的有效定位效应子功能激活所必需的APC是至关重要的。发炎的组织是高度复杂的，并且监测的效率和模式将可能随着细胞因子、趋化因子和细胞浸润的局部阵列而不同。我们已经确定了T细胞运动性的两种可能的调节剂：1）胶原纤维的微观结构和2）浸润性CD 4 + T细胞的效应子谱系。目标1.α v-整联蛋白在炎症真皮中效应T细胞监视中的作用目标2.不同炎症环境中T细胞运动的模式。目标3.炎症中功能不同的效应T细胞活性。效应T细胞的功能是根除病原体，但也有助于免疫病理学。通过确定炎症真皮中T细胞效应活性的关键参数，我们将为新的炎症特异性疗法提供信息。

DESCRIPTION (provided by applicant): Fundamental to immune-mediated protection is the ability of leukocytes to survey barrier surfaces and quickly respond to infection or tissue damage. Signals from cytokines, chemokines and cells (immune and stromal) within the tissue provide critical cues for T cell migration at sites of inflammation, but the mechanics of T cell motility to these signals is poorly understood. Our overall goal is to define mechanistic control points for T cell surveillance within functionally distinct sites of inflammation. In the long-term identification of diverse requirements for T cell function will lead to the selective therapeutic targeting of specific tissues or pathologies. Inflammation results in a change in both the architecture of the tissue as well as its composition. Using intravital multiphoton microscopy of inflamed tissues, we find that interstitial T cell motility in the inflamed skin is highly dependen on alpha-v integrin. Blockade or genetic knock-down of alpha-v halts T cell interstitial movement and also attenuates effector function. We hypothesize that T cell-matrix interactions are critical for lymphocyte surveillance of the inflamed tissue for efficient location of APCs necessary for activation of effector function. The inflamed tissue is highly complex and the efficiency and mode of surveillance will likely differ with the local array of cytokines, chemokines and cellular infiltrate. We have identified two likely modifiers of T cell motility: 1) the microstructure of collagen fibers and 2) the effector lineage of the infiltrating CD4+ T cell. Aim 1. Role of αv-integrins in effector T cell surveillance in the inflamed dermis. Aim 2. Modes of T cell motility n distinct inflammatory environments. Aim 3. Functionally distinct effector T cell activity in inflammation. Effector T cells function to eradicate pathogens but also contribute to immunopathologies. By identifying key parameters for T cell effector activity in the inflamed dermis we will inform new inflammation-specific therapies.