The lung is a fascinating tissue at the level of immune regulation. As barrier to the outside world it is in constant contact with innocuous environmental antigens, but is also the entrance site for many pathogens. Importantly, loss of immune tolerance against environmental antigens, including pollen and house-dust-mite antigens, can cause severe allergic asthma. Dendritic cells (DCs) and Macrophages (MFs) play an essential role in regulation of immune responses. Thus lung DCs and lung MFs appear to mediate two seemingly incompatible functions: maintaining tolerance against harmless environmental antigens while retaining the capacity to response powerfully to invading pathogens. This CIG project is based on the hypothesis that the different functional tasks performed by DCs and MFs in the lungs are in fact mediated by distinct subsets of DCs and MFs. Unfortunately current available research tools cannot properly address the contribution of the individual DC or MF subsets in the regulation of pulmonary immune responses. Therefore, this project proposes to combine state-of-the-art cellular and molecular techniques to generate innovative research tools which will allow to unambiguously study the specific role of the major lung MF subset, i.e. the Alveolar Macrophage (AMFs). We will first identify AMF-specific genes and then generate two knock-in mouse models to unravel the role of AMFs in vivo. This study should lead to a better understanding of the functional role of AMFs in the regulation of pulmonary immune responses, including allergic asthma, airway tolerance and defense against pathogens, which ultimately could lead to the design of more efficient immune intervention strategies to fight lung diseases.