CAREER: Modeling the Physical Regulation of Immune Cell Activation

University Of Tennessee Knoxville, Knoxville TN

Investigators

Abstract

This CAREER award will establish an integrated research and education program that uses theory and computation to elucidate physical mechanisms that regulate immune cell activation. Immune cells such as T cells and B cells use surface receptors to directly engage other cells as they search for molecular signatures of pathogens. An emerging paradigm in immunology is that forces at the cell surface regulate antigen recognition and cell activation. Understanding antigen recognition by T cells and B cells remains one of the most significant unresolved issues in immunology. This project will contribute to fundamental immunological understanding and provide mechanistic guidance for designing immuno-modulatory materials and therapies. The project will leverage a recent initiative to increase the number of Tennesseans with college degrees by engaging high school and community college students in active learning modules. Additionally, first-year undergraduates will be targeted with a new seminar on physical biology, and an emphasis will be placed on engaging students from Tennessee's Appalachian region. These efforts will help to recruit new students into science and engineering, and will expose a broad range of students to the interface of physics and biology. All research students will be involved in educational activities. A graduate student will spend time embedded in an experimental lab, and a workshop organized by the PI will bring theorists and experimentalists together to explore the physical regulation of immune cells. This project will investigate processes that are essential for a proper immune response. It will resolve how membrane and cytoskeletal forces couple with force-dependent dissociation kinetics to influence the dynamics of T cell receptors, elucidate mechanical processes that enhance the ability of B cells to discriminate between and internalize membrane-presented antigens, and characterize how dynamic membrane protrusions on the T cell surface impact the antigen search process. Investigating these processes will result in a new computational framework that can be used to address other emerging questions in immunology and cellular bio-mechanics. Many physical features of antigen recognition are difficult to explore experimentally, and there is no framework for systematically investigating the underlying mechanisms. This project will address this gap by developing computational and theoretical approaches that capture important biophysical interactions at cell-cell interfaces, including stochastic receptor-ligand binding kinetics, membrane mechanics, and actin-mediated forces on the membrane. Such approaches are essential for understanding antigen recognition, as they allow systematic investigation of physical features that are experimentally inaccessible. The computational framework will generate hypotheses that can be experimentally tested, thus providing feedback between theory and experiment. Receptor-mediated interactions between cells are ubiquitous in biology, and as such, the approaches developed in this proposal can be used to study diverse biological phenomena extending far beyond immunology. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster and the Systems and Synthetic Biology clusters in the Division of Molecular and Cellular Biosciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.