Chronic inflammation and dysregulation of the immune response underlie multiple human pathologies, including rheumatoid arthritis and systemic lupus erythematosus. Autoimmune disorders comprise more that 50 distinct diseases and affect about 5% of the population in Europe. Thus, chronic inflammation and autoimmunity are one of the thematic priorities within FP7 Cooperation Health (‘Other Chronic Diseases’).The TAM family of receptor tyrosine kinases - Tyro3, Axl and Mer – together with their activating ligands Gas6 and Protein S - play pivotal roles in immunomodulation and regulation of tissue homeostasis and TAM-deficient mice present systemic inflammation and autoimmunity. However the molecular mechanisms underlying these phenomena remain poorly understood. We have recently discovered that TAM signalling is essential for the development of macrophages in the Marginal Zone (MZ) of the spleen. The heterogeneity of the macrophage lineage has long been recognized, but the developmental origin and function of tissue macrophage subsets have not been clarified.The main objective of this research proposal is to characterize the mechanism/s by which TAM receptors participate in splenic MZ macrophages differentiation and function and ultimately, their contribution to human immune disorders. To achieve this aim I propose to use cutting-edge technologies in gene targeting, cell biology, immunohistochemisty, imaging and bioinformatics. The project will involve numerous mouse models deficient in both the TAM receptors and their ligands and novel in vivo approaches.This proposal, with a great clinical relevance, seeks to link two issues that remain unexplored: 1) the role of TAM receptors in the immune response and autoimmune diseases, and 2) the molecular mechanisms leading to differentiation and specialization of tissue macrophages.The project will be developed in two outstanding centers focused on biomedical research: The Salk Institute (USA) and the IIBM-CSIC (Spain).