Arcs, flows and waves: how the cytoskeleton shapes forces in immune cells

The activation of lymphocytes is an essential step in the adaptive immune response. Lymphocyte activation involves the binding of specialized receptors with antigen on the surface of antigen presenting cells. This leads to changes in cell morphology, large-scale reorganization and dynamics of the cytoskeleton and the movement and assembly of receptors and enzymes into signaling microclusters, which are critical for immune cell activation and the formation of the immune synapse. During this process, cells of the immune system interact with structures that possess a diverse range of physical properties. Coordinated dynamics of the acto-myosin and microtubule cytoskeleton enable the cell to respond these physical stimuli. I will summarize our recent studies that examine how T and B lymphocytes respond to physical cues such as stiffness, topography and ligand mobility. Specifically, I will highlight the distinct roles of the actin and microtubule cytoskeleton in the exertion of mechanical stresses that support signaling activation, receptor movement, microcluster assembly in lymphocytes. We find that traction forces generated by T cells are largely driven by actin dynamics but are also regulated by dynamic microtubules through Rho activation and non-muscle myosin II bipolar filament assembly at the interface between the T cell and antigen presenting surface. Force fluctuation analysis reveals two distinct sources of force generation in T cells and possible interplay between actin and microtubule dynamics. Our studies indicate that cytoskeletal forces may be important for receptor activation in T cells and influence their signaling activity. These findings establish the immune synapse as a mechanochemical module, which enables force generation during signaling activation via exquisitely coordinated spatiotemporal dynamics of cytoskeletal assemblies.