FURIN IN IMMUNITY · PROPROTEIN CONVERTASE FURIN AS A REGULATOR OF IMMUNE RESPONSES

Proprotein convertase furin as a regulator of immune responses

Background: Interleukin (IL)-12 induced T-helper 1 (Th1) polarisation is critical for cell-mediated immune responses against intracellular pathogens. To gain insights into Th1 type immunity we first performed a genome wide analysis (GWA) for IL-12 target genes. This resulted in identification of proprotein convertase (PC) furin as a novel IL-12 target gene. In the subsequent studies we explored how furin regulates T cells in vivo using a T-cell-specific furin knockout. The striking finding is that deletion of furin in T cells results in loss of peripheral tolerance and development of systemic autoimmune disease. Our results also showed that furin is required for proper function of cell-mediated immunity. Objectives: To establish a novel immunology oriented research laboratory at University of Tampere. Specific scientific goals: To evaluate the furin / PC function in immunity: - Aim 1: Investigate the molecular mechanisms of the furin function in T cells - Aim 2: Decipher the role of furin / PCs in human immune-mediated diseases Aim 3: Explore how furin / PCs regulate developing and innate immune responses. Results: The immunoregulation research group was established in 2009 and currently consists of principal investigator (PI), three post-doctorates, three Doctor of Philosophy (PhD) students, one project student and a part-time technician (five females and four male researchers). We have established a high quality immunology research laboratory at University of Tampere, Finland and obtained all necessary permits to perform research on animal models. Our clinical collaborators have acquired ethical permits that enable us to use patient samples in our research. We do not have access to patient information and are not able to identify the individuals in cohorts. Aim 1: We performed microarray experiments using furin-deficient T cells and identified furin dependent signalling pathways in activated T cells. We also used expression correlation analysis to identify novel targets for PCs. We established stable furin expressing cell T lines and performed experiments where we directly identify furin regulators and targets in T cells using proteomics. This work has resulted in one scientific publication, one Master (MS) thesis and two manuscripts that are currently under preparation. Aim 2: We explored the expression of PCs in atherosclerosis and autoimmune diseases and found that furin, but no other PC is overexpressed in the immune cells of human atherosclerotic plaques. We also identified upregulated expressions of several PC target molecules. We continue to explore the dysregulation of furin in the peripheral immune cells in autoimmunity and investigate how the furin genetics associate with atherosclerosis. This work has resulted in one scientific publication and additional work that is in progress. Aim 3: In order to study the role of furin in innate immunity in vivo, we have generated a mouse model where furin is deleted in myeloid cells. Further, to study furin / PC in hematopoiesis and host-defence we have identified PC homologues in zebrafish and banana fly genome and use these as alternative models to study how the PC enzymes regulate the development and function of immunity in infections. This work has resulted in one MS thesis, one manuscript that is submitted and one that is currently in preparation and several others that are more preliminary. Significance and impact Studying furin / PC in immune cells will help to explain the pathogenesis immune-mediated in diseases and understand the regulation of cell-mediated immunity, which is critical for combating against intracellular pathogens, such as M. tuberculosis. In addition, PC enzymes are implicated in the pathogenesis of several other diseases including cander and cystic fibrosis and consequently agents that modulate the PC function are considered for future therapeutics. This research will tackle the cell-type specific function and regulation of PC activity. Our work will enable creating more specific, cell-type specific means for PC regulation, which is instrumental in avoiding unwarranted side effects of general furin / PC inhibitors in clinic. Furthermore, we will identify how PCs and their target proteins are regulated during the course of immune mediated diseases, which can result in development of novel biomarkers. We have established a laboratory that has strong expertise on immunological methodology and expertise in the field. This will continue to strengthen the local and national communities that work on immune-mediated aspects of biomedicine. We have and continue to train new PhD, Doctor of Medicine (MD) and MS students and therefore facilitate the careers of future experts in biomedicine. We have disseminated our results though international peer-reviewed scientific journals, international and national research conferences and workshops. We have also participated in several career development sessions organised by our university and local unions. Project website: http://www.uta.fi/ibt/institute/research/pesu/

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