Manipulating collectivity and Niches for Developing CD8 Immunity

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 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.