Abstract
Abstract T cells require a dynamic cytoskeleton to effectively scan antigen-presenting cells and become fully activated. To study the function of cytoskeletal changes as they occur in real time during T cell activation, we modified an atomic force microscope to deliver antigen via the cantilever, simultaneously ligating T-cell receptors (TCRs) and measuring changes in cytoskeletal mechanics. We show that antigenically naïve T cells are mechanically stiff and their cytoskeletal structures undergo rapid relaxation at the site of TCR ligation. In contrast, antigen-experienced memory and effector T cells are already soft prior to TCR triggering. We found that cytoskeletal relaxation is due to depolymerization of actin, is proportional to antigen dose, and requires proximal TCR signaling pathways but not ICAM-1:LFA-1 interaction. We identified pathways controlling the stiffness of naïve T cells, and blocking these pathways resulted in naïve T cells become soft even prior to TCR triggering. Moreover, these soft yet antigen-inexperienced T cells showed a reduced threshold for allo- and antigen-specific activation compared to controls. Our results highlight the functional importance of cytoskeletal stuctures in tuning T cell responses to spatially localized signals from APCs.
Published Version
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