Spatiotemporal basis of adaptive immunity in the spleen

Adaptive immunity provides essential protection from infectious diseases. This system depends on the ability of lymphocytes to reach distinct compartments within secondary lymphoid organs (SLOs), where specialized cells mediate controlled activation, and where homeostatic survival and peripheral tolerance-promoting cues are presented. Whilst much progress has been made towards defining the mechanisms that regulate these events in lymph-nodes, relatively little is known about how they are orchestrated in the largest SLO in our body, the spleen. Progress in this area lagged largely due to challenges in developing the necessary imaging technology to explore dynamic behaviour of cells within live intact spleens. Our group pioneered cutting-edge imaging approaches that allow us to perform this analysis with high resolution for the first time. Here, we will use a combination of advanced imaging approaches to define the microanatomical structures and molecular mechanisms that facilitate T cell 1) access into splenic T-zones, 2) acquisition of initial activation signals, and 3) egress before/after differentiation into effector cells. These studies will not only resolve fundamental open questions in the field, but also provide a solid foundation for future works aiming to understand how the spleen orchestrates immune responses and how it can be modulated for therapeutic interventions.