The skin is a fascinating tissue at the level of immune regulation. As barrier with the outside world, it is in constant contact with innocuous environmental antigens, but it is also the entrance site for pathogens. Dendritic cells (DCs) play an essential role in initiation and regulation of immune responses. Thus, skin DCs appear to mediate two seemingly incompatible functions: maintaining tolerance against harmless self and environmental antigens constantly present in the skin, while retaining the capacity to induce powerful immune responses to invading pathogens. However, the skin DC population consists of 4 distinct DC subsets. This IEF project is based on the hypothesis that the 4 distinct skin DC subsets possess different regulatory properties. We hypothesize that the different functional tasks performed by skin DCs are in fact mediated by distinct skin DC subsets and speculate that while a particular DC subset may preferentially induce tolerance through induction of regulatory T cells (TREG), other DC subsets may be more efficient for induction of TH1, TH2 or TH17 T cell effector responses to fight invading pathogens. Accordingly, this project proposes to combine state-of-the-art cellular and molecular techniques to unambiguously study the specific role of the 4 skin DC subsets in vivo. We will identify genes underlying the functional diversity of the DC subsets, and in parallel generate an innovative KI mouse model that will restrict the antigen-presenting capacity to one particular skin DC subset at a time, allowing us to unravel the specific role of the distinct skin DC subsets in the induction of TH1, TH2, TH17 and TREG responses in vivo. This study should lead to a better understanding of the functional differences between the distinct skin DC subsets and allow selection of the most optimal DC target for therapy. Such knowledge is mandatory for development of more efficient vaccines and design of new immune intervention strategies to fight skin diseases.