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 re-structuring of the cytoskeleton, and movement of receptors into sub-micron clusters, which are critical for immune cell activation. Antigen presenting surfaces possess a wide variety of physical attributes, which influence cytoskeletal organization and receptor mobility, but how cells respond to these physical cues is not well understood. I will summarize our recent studies that examine how immune cells respond to physical cues such as surface mobility and topography. Regulation of membrane receptor mobility is important in tuning cellular response to external signals, such as during B cell signaling following the binding of B cell receptors (BCR) to antigen. We have used single molecule imaging to examine BCR movement and machine learning techniques to relate receptor trajectories to their signaling states. We find that the dynamic actin network fine-tunes receptor mobility and receptor-ligand interactions, thereby modulating B cell signaling. In vivo, B cells encounter surfaces of antigen presenting cells that are highly convoluted with a wide range of curvatures. We have used nanotopographic surfaces that allow systematic variation of geometric parameters to show that surface features on a subcellular scale influence B cell signaling and actin dynamics. Nanotopography-induced actin dynamics requires BCR signaling, actin polymerization, and myosin contractility. The topography of the stimulatory surface also modulates the distribution of BCR clusters and calcium signaling in activated B cells. Active cytoskeletal control of receptor diffusion may be a general feature that directs how diverse cell types respond to physical stimuli and transduce external signals into internal chemical signals.