Manipulating collectivity and Niches for Developing CD8 Immunity

 描述（由申请人提供）：接种疫苗期间淋巴结中的应答T细胞实际上发生了什么？具体地说：细胞激活的发育中的物理“生态位”的性质是什么？这个群体的成员是谁？连接两个并发反应的关键时间特征是什么？我们打算发现这些问题的答案，作为确定如何实现对病毒的固体CD 8 T细胞免疫的途径。我们将集中精力在淋巴结和肺部，后者将获得我们实验室开发的尖端成像方法。我们和其他人最近使用实时成像来证明淋巴结中的T细胞启动和肺部的重新激活是在高度动态的条件下发生的，这似乎允许正在进行的反应的相当大的混合。我们的实验室已经建立了一系列尖端的成像方法，包括基于多光子的细胞跟踪和突触分析，结合我们在“经典”免疫学检测方面的专业知识，来研究这种“集体”激活;激活占据同一反应性淋巴结的多个T细胞。一个被其他人证实的关键发现是，存在一个“关键分化期”，与单个活化T细胞克隆聚集在一起形成T-T突触介导的接触相一致。基于我们的工作和本领域其他人的工作，我们假设存在天然和合成形式的细胞-细胞相互作用，其可以在诱导CD 8应答期间被利用，并且这些将改变病毒攻击的结果。通过解决这一假设，我们的目标是最终提供一个合理的理解免疫细胞如何共同激活和改善疫苗接种的CD 8反应。

 DESCRIPTION (provided by applicant): What actually happens to responding T cells in the lymph node during vaccination? Specifically: What is the nature of the developing physical `niche' in which cells activate? Who are the members of this cohort and what are the critical temporal features that bridge two concurrent responses? We intend to discover the answers to these questions as a route to determining how to achieve solid CD8 T cell immunity to viruses. We will focus efforts both in lymph node and in the lung and the latter will access cutting-edge imaging approaches developed in our lab. We and others have recently used live imaging to demonstrate that T cell priming in the lymph node and reactivation in the lung take place under highly dynamic conditions that would appear to permit considerable mixing of ongoing responses. Our lab has established a series of cutting-edge imaging approaches including multiphoton-based cell-tracking and synapse-analysis, paired with our expertise in `classical' immunological assays, to study this `collective' activation; activation of multiple T cells that occupy the same reactive lymph node. A key finding that is corroborated by others is that there is a `Critical Differentiation Period' that coincides with individual activating T cell clones comig together into a T-T synapse-mediated contact. Based on our work and that of others in the field, we hypothesize that there are both natural and synthetic forms of cell- cell interactions that can be leveraged during elicitation of a CD8 response and that these will alter the outcome of a viral challenge. Through addressing this hypothesis, we aim to finally provide a rationale understanding of how immune cells co-activate and improving vaccination for CD8 responses.