Local regulation of cytotoxic T cell function in the tumor stroma

申请者开始在德国接受儿科和实验外科培训。通过相关问题 对于外科疾病状态下的白细胞迁移，如休克和缺血再灌注，他得出了一个 对疾病的基础科学观点。他已经来到美国开始免疫学的博士后工作 从那时起，他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 功能通过迁移和蜂窝交互来实现。具体地说，他通过 使用活体显微镜方法直接进行活体可视化。他的长期职业目标是建立 他是一家基础研究机构的独立研究员，对免疫学有着浓厚的兴趣。 细胞毒性T淋巴细胞(CTL)通过接触依赖在抗肿瘤免疫中的重要作用 细胞毒性。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 目前还不清楚细胞毒性在多大程度上直接赋予肿瘤细胞或 肿瘤间质。这个项目将通过CTL-Tumor的直接动态可视化来解决这些公开的问题 体内细胞相互作用与肿瘤细胞死亡。 效应性T细胞受外周耐受机制控制，包括调节性T细胞的活动 (Treg)。目前尚不清楚Treg通过什么机制和水平控制免疫反应。这 研究项目将调查Treg抑制CTL效应器功能对抗肿瘤的假设 在时间和空间上受到限制的方式。多光子活体显微镜产生实时记录 以亚细胞分辨率迁移细胞，并将用于解决以下具体目标：1)至 描述CTL和体内肿瘤细胞的空间、行为和功能关系。)检视 Treg是否以及如何控制肿瘤中的CTL动态平衡、行为和功能。拟议中的实验将 生成外周组织中CTL功能的面向机制的大纲。 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，如在自身免疫中 疾病。

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.