Regulation of effector T cell migration within inflamed tissues

描述(由申请人提供)：免疫介导保护的基础是白细胞观察屏障表面并对感染或组织损伤做出快速反应的能力。细胞因子、趋化因子和组织内细胞(免疫和间质)的信号为T细胞在炎症部位的迁移提供了关键信号，但T细胞对这些信号的运动机制尚不清楚。我们的总体目标是在功能不同的炎症部位确定T细胞监测的机械控制点。在长期的识别中，对T细胞功能的不同需求将导致对特定组织或病理的选择性靶向治疗。炎症会导致组织的结构和组成发生改变。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间质T细胞的运动高度依赖于α-v整合素。阻断或基因敲除α-v可阻止T细胞间质运动，也可削弱效应器功能。我们假设T细胞与基质的相互作用对炎症组织的淋巴细胞监测至关重要，以有效定位激活效应器功能所必需的APC。炎症组织是高度复杂的，监测的效率和模式可能会随着局部细胞因子、趋化因子和细胞浸润的不同而不同。我们已经确定了T细胞运动的两个可能的修饰物：1)胶原纤维的微结构和2)浸润性的CD4+T细胞的效应谱系。目的1.αv-整合素在炎症真皮效应T细胞监测中的作用。目的2.T细胞在不同炎症环境中的运动方式。目的3.炎症中不同功能的效应T细胞活性。效应器T细胞的功能是根除病原体，但也对免疫病理有贡献。通过确定炎症真皮中T细胞效应器活性的关键参数，我们将提供新的炎症特异性治疗方法。

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.