Schwartzberg/Burkhardt

Project Title

Regulation of T cell migration by inositol lipids and the cortical cytoskeleton

NIH Mentor

Pamela Schwartzberg

Penn Mentor

Janis Burkhardt

Project Details

T cell migration through complex body tissues is coordinated by signaling through chemoattractant receptors and integrin cell adhesion molecules, which direct specific cytoskeletal rearrangements that are critical for T cell homeostasis, migration, and function. In many cases, this process involves signaling-induced changes in phosphoinositides in the inner leaflet of the plasma membrane, which create binding sites for cytoplasmic molecules that induce localized integrin activation and actin responses. Dysregulation of these events is associated with several primary immunodeficiency diseases. Moreover, proteins that regulate these events can be targeted to modulate T cell trafficking in therapeutic settings. Our labs have been studying two phosphoinositide binding proteins, Rasa3 (a Rap1GAP) and moesin (a cortical actin linker protein). Deletion of either of these molecules results in increased integrin-dependent adhesion and increased directional migration in vitro. In vivo, T cells lacking these proteins exhibit marked defects in lymph node entry and egress and defective responses to immunization. We are interested in understanding how these proteins function to control cell motility, whether their signaling pathways interact and how they affect the ability of T cells to migrate and respond appropriately to immune challenges in vivo.