Backgound: Interleukin (IL)-12 induced T helper (Th) 1 polarization is critical for adequate cell-medated immune responses against intracellular pathogens such as M. tuberculosis. To gain insights into Th1 type immunity I performed a genome wide analysis for IL-12 target genes. The results unequivocally identified proprotein convertases (PC) furin as a novel IL-12/Stat4 target gene. Furin has been previously linked to the pathogenesis of several diseases including metastatic cancers, cystic fibrosis and infectious diseases. Consequently, furin inhibitors have been proposed as possible therapies for such diseases. I have explored furin’s physiological role in T cells using a T cell-specific furin knockout. The striking finding is that conditional deletion of furin in T cells results in loss of peripheral tolerance and systemic autoimmune disease. Objective: To evaluate the role of furin and as a regulator of immune responses; specific aims:1. Furin’s molecular mechanisms of action in T cells, 2. The role for furin in diseases of broken peripheral tolerance, 3. Furin as a regulator of innate immunity. Significance: Studying furin in T cells will help to explain the pathogenesis impaired peripheral tolerance observed in diseases like IBD and celiac disease, and understand the regulation of Th1 type immune responses that are critical in combating intracellular pathogens, such as M. tuberculosis. On the other hand, furin plays also an important role in the activation of pathogens (e.g. HIVgp160, B. Athracii toxins) and upregulates metastatic activity of cancers and pathogenesis of cystic fibrosis. This research will tackle the cell-type specific function and regulation of proportein convertase activity by identifying novel furin targets and regulators of its activity. This will enable creating more specific, cell-type specific means for furin regulation; this will be instrumental in avoiding unwarranted side effects of general furin inhibitors in clinic.