One of the central challenges in biology is to elucidate how microenvironments modulate molecular mechanisms and thus global cellular function. The Lillemeier lab studies signal transduction in the plasma membrane of T lymphocytes (T cells) upon their activation by Antigen Presenting Cells (APCs). Major rearrangements of signaling molecules take place during this event, which is most dramatically seen in the formation of signaling microclusters and the immunological synapse (see movie). The lab uses cutting edge super-resolution and dynamic fluorescence microscopy techniques (e.g. PALM and FCCS) in combination with traditional biochemical and molecular biological approaches to study the molecular patterns that regulate and are required for T cell activation and function.
We have found a new type of plasma membrane domains, termed protein islands, and the specific segregation of all membrane-associated proteins within them. These findings inspire a new and unsuspected role for the plasma membrane in the spatio-temporal regulation of T cell activation and membrane biology in general. Specifically, we found that signaling cascades are prearranged into 'building blocks', through the localization of signaling molecule subsets within specific protein islands. Redistribution of these protein islands in response to stimuli can lead to either concatenation and assembly of signal transduction pathways or their dissociation and disassembly. These rearrangements are not diffusion limited but active and directed through cytoskeletal forces and pathway-specific protein-protein interactions.
Movie: A primary T cell becomes activated on a glass supported lipid bilayer containing its natural ligands. T cell receptor (TCR) molecules, labeled with enhanced green fluorescent protein (eGFP), form microclusters at the entire the contact site between T cell and bilayer. TCR microclusters are transported towards the center of the contact site in an actin dependent fashion and form the center of an immunological synapse. The movie was acquired in total internal reflection (TIRF) mode to eliminate intracellular fluorescence.
© 2014 Salk Institute for Biological Studies
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