Tissue regulation of T cell function

描述（由申请人提供）：许多病原体进入并驻留在皮肤和肺的屏障组织中。病原体控制最终需要募集和激活免疫效应子到特定的感染组织微环境。虽然我们对淋巴组织中效应T细胞的产生已经有了很多了解，但对于效应T细胞一旦离开淋巴结后的命运，仍然存在很大的知识缺口。然而，正是在发炎的组织环境中，T细胞必须介导其效应子功能，包括细胞因子分泌和细胞溶解，以清除感染。核心假设是特定组织和局部炎症环境将塑造T细胞募集和效应子功能。这种组织控制可能会影响 免疫反应的强度和功能多样性。优化组织中的T细胞功能对于病原体清除和避免附带损伤至关重要。该提案的目标是定义检查点并确定在炎症部位指导成功免疫的分子相互作用。该计划项目的目标是汇集迁移和效应功能方面的科学专业知识，使用尖端的活体成像方法来解决感染组织中的基本效应T细胞过程。当效应T细胞进入发炎组织时，它们遇到的组织环境已根据病原体和相应炎症的类型而发生差异性改变。T细胞感知和解释不同炎症环境的能力以及对有效病原体清除的影响知之甚少。项目1（Minsoo Kim博士）解决了中性粒细胞如何改变微环境以及T细胞如何整合多种组织特异性炎症信号。项目2（Deborah Fowell博士）确定了改变的环境如何控制效应T细胞迁移和调查组织中携带抗原的APC/感染细胞所使用的机制。项目3（大卫Topham博士）的重点是炎症肺组织如何改变CDS迁移和影响流感感染的长期组织记忆的发展。这些过程对于清除病原体至关重要，但也支持在慢性炎症、自身免疫和过敏环境中激活免疫力。使用创新的工具原位调制和可视化的免疫反应在皮肤和肺，我们将定义的分子参数效应T细胞的运动和功能在不同部位的炎症。

DESCRIPTION (provided by applicant): Many pathogens enter and reside in barrier tissues of the skin and lung. Pathogen control ultimately requires the recruitment and activation of immune effectors to specific infected tissue micro-environments. While we have gained much insight into effector T cell generation in lymphoid tissues there exists a significant knowledge gap on the fate of effector T cells once they leave the lymph node. Yet it is within the inflamed tissue milieu that T cells must mediate their effector functions, including cytokine secretion and cytolysis, to clear the infection. The central hypothesis is that the specific tissue and the local inflammatory milieu will shape T cell recruitment and effector function. Such tissue-control is likely to impact the magnitude and functional diversity of the immune response. Optimizing T cell function in tissues is critical for pathogen clearance and the avoidance of collateral damage. The goal of this proposal is to define the checkpoints and identify molecular interactions that guide successful immunity at sites of inflammation. The objective of this Program Project is to bring together scientific expertise in migration and effector function to address fundamental effector T cell processes in infected tissues using cutting-edge intra-vital imaging approaches. When effector T cells enter the inflamed tissue they encounter a tissue environment that has been differentially altered depending on the type of pathogen and corresponding inflammation. The ability of T cells sense and interpret different inflammatory environments and the impact on effective pathogen clearance are poorly understood. Project 1 (Dr. Minsoo Kim) addresses how neutrophils modify the micro-environment and how T cells integrate multiple tissue-specific inflammatory cues. Project 2 (Dr. Deborah Fowell) determines how the altered milieu controls the mechanisms used by effector T cells to migrate and survey the tissue for antigen-bearing APC/infected cells. Project 3 (Dr. David Topham) focuses on how the inflamed lung tissue modifies CDS migration and impacts on the development of long-term tissue memory to influenza infection. These processes are critical to the clearance of pathogens but also support the activation of immunity in chronic inflammation, autoimmune and allergic settings. Using innovative tools for in situ modulation and visualization of immune responses in the skin and lung we will define the molecular parameters for effector T cell movement and function at distinct sites of inflammation.