Dendritic cells (DC) are a heterogeneous population of rare leukocytes highly specialized for immune-surveillance, and the induction and regulation of primary immune responses. This unique capacity reflects their ability to continuously sample the microenvironment and ingest foreign and self-antigens. After encountering a """"""""danger"""""""" stimulus in the form of microbes, inflammatory molecules or allergens, DC transform into potent stimulatory cells and migrate to secondary lymphoid tissues, where they trigger the activation of antigen-specific effector T cells. The signaling pathways that underlie these processes are undoubtedly complex, but intracellular calcium appears to play a crucial role. We have recently characterized two novel calcium signaling pathways in DC. First, we have identified the skeletal muscle-type ryanodine receptor (RyR1) in DC. RyR1 is a massive intracellular channel that can amplify small calcium transients within a cell to produce much larger, sustained calcium rises. Second, we have demonstrated that calcium fluxes trigger rapid secretion by DC. Such pathways enable DC to respond rapidly to external stimuli, and release autocrine and paracrine signaling factors including exosomes and leaderless secretory proteins. The goal of this proposal is to determine the RyRl-calcium regulated pathways in DC. We hypothesize that RyR1 integrates diverse cellular stimuli, and mediates the calcium pathways that drive DC function. An inter-disciplinary approach is outlined to investigate the properties of these calcium signaling mechanisms and understand how they participate in DC biology. We will accomplish the objectives of this proposal by pursuing the following specific aims:
Aim 1 is designed to determine the role of RyR1 during DC development and function.
Aim 2 tests the impact of endogenous and pharmacologic activators of RyR1 on DC.
In Aim 3, we will elucidate the role of calcium-triggered secretion in DC.
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