Cellular and molecular mechanisms of block of dendritic cell development in growth factor receptor mutant mice

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Dendritic cells are immuno-modulatory cells that are crucial for the instigation of immune responses in benefit for health (pathogen defense) but also in disadvantage for health (autoimmunity). However, antigen presentation by non-activated dendritic cells induces tolerance to any antigen including self-antigens, suggesting that dendritic cell homeostasis is one putative mechanism that regulates instigation, length and intensity of immune reactions. Therefore, the identification of growth requirements supporting or suppressing the development and maintenance of dendritic cells in vivo holds the promise to understand cellular mechanisms regulating immune responses. It is to date unclear which growth requirements are necessary for normal dendritic cell development in vivo. We recently reported on the important role for the growth factor receptor fetal liver kinase 2 (Flk2) during final stages of dendritic cell development in peripheral lymphoid organs. We now generated near complete dendritic cell null mice and thereby identified the two crucial growth factor receptors for dendritic cell development in vivo. In this proposal we describe a research plan that aims at analyzing the cellular and molecular basis of this developmental defect and at linking defective dendritic cell homeostasis to the maintenance of tolerance during adult life.