Kinetics and Mechanisms of Steady-State Dendritic Cell Migration

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Dendritic cells (DCs) are professional antigen presenting cells primarily responsible for the initiation of new immune or tolerogenic responses. They act as a crucial link between the innate and adaptive immune systems. DC migration from peripheral tissues into lymph nodes can be induced by inflammatory stimuli and this process is crucial for the induction of immune responses. However, in steady-state, DC migration occurs constitutively and has an important role in the initiation of peripheral immunological tolerance - a process crucial for the prevention of deleterious inflammation. This is most notable in the intestine, where a failure of peripheral tolerance can lead to the development of inflammatory bowel diseases (IBD) or food allergy. Surprisingly, the mechanisms controlling DC migration in steady state and thereby tolerogenic immune responses are largely unknown.To mechanistically dissect the process of steady state DC migration, we developed a range of novel, dedicated tools. Cannulation of the pseudo-afferent lymph will allow us to isolate DCs in the process of migration, while a novel transgenic mouse model, the CCR7-GFP reporter, enables the identification of DCs which are about to exit peripheral tissues. In addition, using in vivo photoconversion, we will be able to track and quantify DC migration. Our initial results show that steady-state intestinal DC migration is a highly dynamic process which leads to the almost complete turnover of the migratory DC compartment in intestine-draining lymph nodes every 24h. This remarkable investment of resources further underlines the importance of steady-state DC migration. Furthermore, we found that intestinal DCs, in the stages immediately preceding egress from tissue, already adopt a distinct phenotype. Characterising these initial changes will enable us to dissect the molecular mechanisms controlling the process of DC migration. In this proposal we aim to: 1) Determine the kinetics of steady-state DC life cycle 2) Characterise the molecular mechanisms controlling steady-state DC migration. 3) Determine the fate, location and function of steady-state migrating DCs in the LN. This project will generate a comprehensive model of steady state DC migration and its regulation. We expect that such understanding, in addition to characterizing a major biological process, may provide information that will affect the future development and design of treatments for inflammatory diseases, particularly in the context of the intestinal tract.