Tissue Regulation of T Cell Function

项目总结/摘要-总体 病原体感染引发局部炎症，导致先天性效应细胞的流入和加工 趋化因子，细胞因子和其他可溶性介质。进入受感染组织的T效应细胞遇到了一个 根据病原体的类型从基础状态发生差异性改变的组织环境 和相应的先天性炎症反应。效应T细胞必须通过这个间隙迁移 为了定位抗原呈递细胞和感染的靶细胞并接收效应子功能的激活信号， 病原体清除和组织记忆的建立。虽然这些复杂的框架 建立了先天细胞、可溶性介质和组织结构之间的相互作用， T细胞感知和解释不同的炎症环境以及对免疫功能的影响是 不太了解。然而，它们必须在受感染的外周组织内执行其效应器功能 来清除病原体它也是在外周组织中，其中失调的炎症导致免疫反应。 病理学;从自身免疫到心血管疾病。使用创新工具进行原位调制， 可视化小鼠皮肤和肺部的免疫反应，该计划项目的目标是 深入了解控制感染或感染后T细胞募集、迁移和激活的信号， 皮肤和肺的发炎组织。上一个资助周期已经确定了T细胞免疫的新机制。 募集、间质迁移以及效应子和组织记忆亚群的定位。这一建议建立 在炎症部位的这些分子检查点上，以确定来自先天细胞的外部信号 组织微环境决定了保护性免疫中效应T细胞的位置和功能。 项目1。中性粒细胞反应的解决，有效的T细胞功能和组织修复。Minsoo Kim博士。 假设：中性粒细胞死亡不是被动的，而是死亡中释放的特定因子 嗜中性粒细胞促进有效的T细胞活化和组织修复。 项目2.通过细胞因子/趋化因子依赖的炎症部位的T细胞活化的空间优化 细胞聚类黛博拉·福尔博士。假设：外周T细胞活化发生在富含趋化因子的 血管周围簇，其成核并放大T细胞募集/活化以有效清除病原体。 项目3。组织驻留记忆性CD 8 + T细胞的形成、定位、运动性和功能 流感感染。大卫·托彭博士。假设：特定的TRM子集占据不同的空间 在呼吸道中的微环境，赋予功能的差异，保护免受流感感染。 项目4。T细胞迁移的机制。帕特里克奥克斯博士。假设：不同免疫细胞的迁移 细胞沿着一个单一的连续体，不同之处仅在于粘附和力产生的相对贡献。 核心A。行政，福厄尔D. J.;核心B。图像，Kim M.;核心C。试剂，米勒J。

PROJECT SUMMARY/ABSTRACT – OVERALL Pathogen infection initiates local inflammation that leads to the influx of innate effector cells and elaboration of chemokines, cytokines and other soluble mediators. T effector cells entering the infected tissue encounter a tissue environment that has been differentially altered from the basal state depending on the type of pathogen and corresponding innate inflammatory response. Effector T cells must migrate through this interstitial space to locate antigen-presenting cells and infected target cells and receive activation signals for effector function, pathogen clearance and establishment of tissue memory. Although the framework of these complex interactions between innate cells, soluble mediators and tissue architecture is established, the ability of effector T cells to sense and interpret different inflammatory environments and the impact on immune function are poorly understood. Yet, it is within the infected peripheral tissues that they must execute their effector function for pathogen clearance. It is also within peripheral tissues where dysregulated inflammation leads to immune pathology; from autoimmune to cardio-vascular disease. Using innovative tools for in situ modulation and visualization of immune responses in the skin and lung of the mouse the goal of this Program Project is to gain insight into the signals that control T cell recruitment, migration and activation in infected or inflamed tissues of the skin and lung. The previous funding cycle has identified new mechanisms of T cell recruitment, interstitial migration, and positioning of effector and tissue memory subsets. This proposal builds on these molecular checkpoints at sites of inflammation to determine how external signals from innate cells and the tissue microenvironment shape the position and function of effector T cells for protective immunity. Project 1. Resolution of neutrophil response for effective T cell functions and tissue repair. Dr Minsoo Kim. Hypothesis: that neutrophil death is not passive, but rather, that the release of specific factors from dying neutrophils promotes effective T cell activation and tissue repair. Project 2. Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering. Dr Deborah Fowell. Hypothesis: that peripheral T cell activation occurs in chemokine-rich peri-vascular clusters that nucleate and amplify T cell recruitment/activation for efficient pathogen clearance. Project 3. Formation, Positioning, Motility, and Function of Tissue Resident Memory CD8+ T cells After Influenza Infection. Dr David Topham. Hypothesis: specific TRM subsets occupy distinct spatial microenvironments in the airway that confer functional differences in protection against influenza infection. Project 4. Mechanics of T cell migration. Dr Patrick Oakes. Hypothesis: that migration of different immune cells lies along a single continuum, differing only in relative contributions of adhesion and force generation. Core A. Administrative, Fowell D.J.; Core B. Imaging, Kim M.; Core C. Reagents, Miller J.