Molecular mechanism regulating LFA-1 de-adhesion during T cell migration

• Antragstellerin: Dr. Melanie Laschinger
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2009 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 160178046

T cells use the integrin LFA-1 to migrate across the endothelial vessel wall into lymphoid tissue and, following infection, into sites of inflammation. On circulating cells LFA-1 is expressed in an inactive state and needs to be activated to bind its ligand ICAM-1. Our data show that migration along the vasculature (crawling) is regulated through a cycle of LFA-1 mediated adhesion and de-adhesion. We provide evidence that after having passed high endothelial venules LFA-1 activity needs to be switched off within the lymphoid tissue to allow T cells to migrate into the T cell zone. Whereas the mechanisms inducing adhesion are well established, the molecular cascade inducing de-adhesion of LFA-1 remains poorly understood. Aim of the present proposal is to define the molecular mechanism of LFA-1 de-adhesion. Based on our preliminary data we postulate that LFA-1 regulates via the serine/threonine phosphatase PP1 the activity of ERM-proteins and hence the cytoskeletal reorganisation that is mandatory for de-adhesion and T cell migration. Elucidating the pathways regulating T cell polarity and integrin dependent T cell migration will help us to mechanistically understand cell migration and has the potential to better control pathophysiolgical situations like graft rejection or autoimmune diseases.

• DFG-Verfahren: Sachbeihilfen