Grant: Discovery Grants Program - Individual

Cells of the immune system, such as T and B lymphocytes, sense their environment using an array of specialized surface receptors. Upon binding a suitable foreign substance, these receptors generate intracellular signals, allowing the cell to respond appropriately to a given stimulus. During cellular stimulation, surface receptors (such as the T and B cell receptors - TCR and BCR) are commonly observed to reorganize their movement and location. For example, TCR and BCR are observed to form sub-micrometer clusters on the cell surface. Our understanding of how receptor signaling leads to changes in receptor motion, and how these dynamic changes affect subsequent signaling, is a key part of our knowledge of the processes governing lymphocyte activation. This proposal focuses on the use of single particle tracking (SPT) as a tool to probe the spatial dynamics of lymphocyte surface receptors. We will develop experimental and theoretical tools and perform a program of experiments designed to shed light on the relationship between receptor signaling and receptor dynamics on the cell surface. To perform the experiments, we will label individual receptors with a fluorescent tag and track the movements of individual molecules using microscopy. Motion data will then be analyzed using novel statistical approaches already under development. These experiments will allow us to clearly understand the strengths and limitations of SPT in this context. The information from these experiments will advance our basic understanding of immune cell activation. This is important in understanding autoimmune diseases and the immune response to viruses, for instance. Further, certain classes of drugs work in a way that mimics part of the immune system, and understanding the physical parameters that govern this may become an important part of designing new drugs.