How immune cells respond to physical cues – the role of cytoskeletal dynamics

The activation of lymphocytes, an essential step in the adaptive immune response, involves the binding of specialized receptors with antigens. This results in large-scale dynamics and reorganization of the cytoskeleton, and assembly of receptors into signaling microclusters, which are critical for immune cell activation and formation of the immune synapse. The cytoskeleton plays distinct roles in the exertion of mechanical stresses that drive receptor activation, spatial reorganization and assembly of signaling proteins in lymphocytes. Forces exerted by T cells on the antigen presenting surface arise due to the dynamics of actin polymerization, myosin motor activity and microtubule dynamics. Force fluctuation analysis reveals distinct contributions of these cytoskeletal elements to force generation in T cells. Our results also indicate a mechanical coupling between the actomyosin and microtubule systems whereby different actin structures influence microtubule dynamics in distinct ways. Microtubule growth dynamics at the IS are differentially modulated by distinct actin nucleators. Furthermore, microtubule filament dynamics and shape deformations are actively modulated by actin polymerization and myosin activity in the immune synapse. While antigens binding to T cell receptors are the primary drivers of lymphocyte signaling, additional factors serve to modulate activation. I will summarize our studies that reveal how physical cues such as stiffness and topography modulate T cell activation by regulating the coordinated dynamics of the acto-myosin and microtubule cytoskeleton. Finally, I will discuss our recent work that reveals how cell-secreted chemicals or cytokines control actin and microtubule dynamics and cellular force generation in killer T lymphocytes. Together, these studies reveal how different regulators of signaling work in concert with the cytoskeleton to control the immune response.