Mobility, organization and signalling of immune cell surface receptors

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B cells are an essential part of the adaptive immune response. In vivo, B cells can become activated (leading to proliferation and secretion of antibodies that bind to and neutralize invading pathogens) after binding specific antigens with their B cell receptors (BCR). B cell surface receptors are known to spatially organize themselves during antigenic signal detection. Therefore, in order to obtain a proper understanding of B cell activation, we need to study the motion of surface molecules such as BCR and relate their motion to the biochemical reactions within the cell that lead to cell activation. ******This proposal focuses on the use of cutting-edge single particle tracking and super-resolution microscopy as tools to probe the nanometer-scale spatial dynamics of B cell surface receptors and the impact of those dynamics on cellular activation. To perform the experiments, we will label individual receptors with fluorescent tags and track the motion and spatial distribution of individual molecules using microscopy. These experiments will allow us to clearly understand the strengths and limitations of single particle tracking and super-resolution microscopy in this context. A second major part of this proposal is to develop new mathematical and statistical models that will help us to synthesize the experimental data into a coherent, quantitatively accurate picture.******The information from these experiments will advance our basic understanding of B cell activation. This is important in understanding autoimmune diseases and the immune response to pathogens, for instance. Certain classes of drugs for treatment of autoimmune disorders and cancers work in a way that mimics part of the immune system, and understanding the physical parameters that govern this complex system will allow us to understand the mechanism of existing drugs and potentially propose new therapies. Developing our expertise in advanced microscopy will lead to new collaborative work with cell biologists and immunologists around the world. A final important impact of the work will be the ongoing training of researchers who are conversant with experimental and theoretical/computational techniques in immunology and cell biology.