Cells have the remarkable ability to sense and respond to the mechanical properties of their environment. This mechanosensing ability is essential for many phenomena ranging from the movement of individual cells, cell differentiation and fate choice as well as large-scale tissue rearrangement during development. Recent work has shown that immune cells are responsive to their mechanical environment and this mechanosensitivity tunes their ability to respond to infectious agents. This project aims to understand how internal forces generated by the biopolymer networks of actin filaments and the motor protein, myosin, enable the T lymphocyte to modulate biochemical signaling, enhancing our understanding of how mechanical stimuli and biochemical signaling are coupled during the immune response using concepts and tools from physics and engineering. This work has potential implications for improving the design of artificial antigen-presenting devices that can enhance the efficiency of immunotherapies against pathogens and tumors. The PI will develop a lecture and laboratory course in cell mechanics, in which concepts from topics such as statistical and continuum mechanics will be used to explain biological processes. The PI will encourage minority and high school students from the area to participate in research. The PI will organize biophysics laboratory demonstrations as part of the Summer Girls Program at the University of Maryland to encourage participation of female students in science and technology fields.
The binding of T cell receptors (TCRs) to antigen-derived peptides results in the formation of dynamic protein assemblies, called signaling microclusters, that serve as the initiating points for T cell activation and the first step of the adaptive immune response. Recent work has revealed that T cells are responsive to the mechanical environment on which antigens are presented and that physical forces can trigger T cell activation. However, the mechanisms by which T cells combine mechanical and biochemical signals to carry out specific functions is not well understood. This project will test the hypothesis that signaling microclusters are responsive to forces, acting as dynamic mechanosensors, thereby allowing the cell to respond and sense the physical properties of the antigen-bearing surface. The PI aims to elucidate how cellular forces regulate the assembly of signaling assemblies at activated T cell receptors (Aim 1), to determine the molecular linkages between cytoskeletal forces and T cell signaling activation (Aim 2) and how these forces more globally lead to activation at the level of the whole cell (Aim 3). This study will reveal common principles in the mechanisms of receptor-mediated sensing of the mechanical environment and the more commonly studied integrin-mediated mechanosensing.
