Local regulation of cytotoxic T cell function in the tumor stroma

描述(申请人提供)：申请人在德国开始接受儿科和实验外科培训。通过与外科疾病状态下的白细胞迁移有关的问题，如休克和缺血-再灌注，他得出了对疾病的基本科学观点。他来到美国开始了免疫学的博士后工作，并从那时起一直致力于这一领域的基础研究。他通常感兴趣的是白细胞是如何通过迁移和细胞相互作用实现功能的。具体地说，他使用活体显微镜方法通过直接活体可视化来研究T细胞功能。他的长期职业目标是在一家对免疫学有浓厚兴趣的基础研究机构确立自己的独立研究员身份。细胞毒性T淋巴细胞(CTL)通过接触性细胞毒作用在抗肿瘤免疫中发挥重要作用。CTL在体内直接杀伤肿瘤细胞的单细胞动力学和效率尚不清楚，也不清楚在多大程度上直接赋予肿瘤细胞或肿瘤间质成分细胞毒性。这个项目将通过在体内直接动态可视化CTL-肿瘤细胞相互作用和肿瘤细胞死亡来解决这些开放的问题。效应性T细胞受外周耐受机制的控制，包括调节性T细胞(Treg)的作用。目前尚不清楚Treg通过什么机制和水平控制免疫反应。本研究项目将探讨Treg以时间和空间受限的方式抑制CTL效应抗肿瘤功能的假说。多光子活体显微镜以亚细胞分辨率产生迁移细胞的实时记录，并将用于解决以下特定目标：1)研究CTL与体内肿瘤细胞的空间、行为和功能关系。研究Treg是否以及如何控制肿瘤中CTL的动态平衡、行为和功能。建议的实验将产生一个面向机制的外周组织中CTL功能的轮廓。这项研究的目的是增加我们对免疫反应如何调节的总体理解。这些知识是合理设计治疗方案的先决条件，该方案旨在增强所需的免疫反应，如针对肿瘤，或抑制不希望的反应，如自身免疫性疾病。

DESCRIPTION (provided by applicant): The applicant started training in pediatric and experimental surgery in Germany. Through questions related to leukocyte migration in surgical disease states, such as shock and ischemia-reperfusion, he arrived at a basic science perspective on disease. He has come to the U.S. to start post-doctoral work in Immunology and has since then committed himself to basic research in this field. His general interest is how leukocyte function is enabled through migration and cellular interaction. Specifically, he studies T cell function through direct in vivo visualization using intravital microscopy approaches. His long-term career goal is to establish himself as an independent investigator at a basic research institution with a strong interest in immunology. Cytotoxic T lymphocytes (CTL) critically contribute to anti-tumor immunity through contact-dependent cytotoxicity. The single-cell kinetics and efficiency of direct killing of tumor cells by CTL in vivo are not known and it is unclear to what extent cytotoxicity is directly conferred upon either tumor cells or constituents of the tumor stroma. This project will address these open questions by direct dynamic visualization of CTL-tumor cell interaction and tumor cell death in vivo. Effector T cells are controlled by peripheral tolerance mechanisms, including the action of regulatory T cells (Treg). It is not known by what mechanisms and at what levels Treg control immune responses. This research project will investigate the hypothesis that Treg suppress CTL effector function against tumors in a temporally and spatially restricted manner. Multiphoton intravital microscopy generates real-time recordings of migrating cells at subcellular resolution and will be used to address the following specific aims: 1.) To characterize the spatial, behavioral, and functional relationship of CTL and tumor cells in vivo 2.) To examine if and how Treg control CTL homeostasis, behavior and function in tumors. The proposed experiments will generate a mechanism-oriented outline of CTL function in peripheral tissues. The aim of this study is to increase our general understanding of how immune responses are regulated. Such knowledge is prerequisite for the rational design of therapeutic regimen designed to either enhance desired immune responses, e.g. against tumors, or suppress undesired responses, such as in autoimmune diseases.