Spatiotemporal regulation of t-cell priming
The initiation of adaptive cellular immunity requires antigen-specific interactions between Dendritic cells (DC) and naive CD8 T cells in secondary lymphoid organs. We aim to understand how the dynamic migratory behavior of myeloid and lymphoid cells is coordinated to ensure that “the right cells” communicate at “the right time” in “the right place” to enable robust immune responses. Using intravital microscopy, we have recently identified a critical phase (“Step 2”) of T cell priming that follows the initial encounter of DC and CD8 T cells and is essential to develop protective immunity.

The aim of this proposal is to identify the cellular and molecular mechanisms regulating T cell differentiation during Step 2. We will employ a newly developed imaging method (“Net-Vis”) to investigate how key elements of Step 2 (XCR1 DC) receive antigenic and inflammatory “information” within a network of myeloid cells. Next, we will test a novel model of T cell priming in which stepwise relocalization to multicellular clusters within the LN orchestrates T cell differentiation. Combining deep-tissue intravital microscopy, “Niche-seq” and novel genetic approaches, we will identify the cellular players and molecules guiding these processes and test their mechanistic implications. Finally, we will investigate the identity and mechanisms of Foxp3+ T cells that co-regulate CD8 T cell activation and differentiation during Step 2. 

In summary, we will exploit an array of innovative imaging, spatiotemporal transcriptomics and genetic approaches to investigate novel fundamental aspects of CD8 T cell priming during a newly discovered distinct phase of T cell activation and differentiation. Investigating the mechanisms that guide these central steps in adaptive immunity is anticipated to reveal new avenues for the therapeutic manipulation of immune responses against infection and cancer.