Manipulating collectivity and Niches for Developing CD8 Immunity

 描述(申请人提供)：在接种疫苗期间，淋巴结内的反应T细胞究竟发生了什么变化？具体地说：在细胞激活的发展中的物理“生态位”的性质是什么？谁是这个队列的成员？连接两个并发响应的关键时间特征是什么？我们打算找到这些问题的答案，以此作为确定如何实现对病毒的可靠CD8T细胞免疫的途径。我们将把重点放在淋巴结和肺上，后者将使用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技术证明，T细胞在淋巴结中的启动和在肺中的重新激活发生在高度动态的条件下，似乎允许相当多的正在进行的反应的混合。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，再加上我们在经典免疫学分析方面的专业知识，来研究这种“集体”激活；即激活占据同一反应性淋巴结的多个T细胞。其他人证实的一个关键发现是，存在一个“关键分化期”，即单个激活的T细胞克隆聚集在一起，形成T-T突触介导的接触。基于我们和该领域其他人的工作，我们假设在CD8反应的激发过程中可以利用自然形式和合成形式的细胞-细胞相互作用，这些形式将改变病毒挑战的结果。通过解决这一假说，我们的目标是最终为免疫细胞如何共同激活和改进CD8反应的疫苗接种提供一个基本的理解。

 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.