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Controlling how a T cell hugs
CD4+ T cells that have not encountered antigen are called naïve cells and require a stronger stimulus to become activated than do effector or memory CD4+ T cells, which have previously encountered antigen. Consequently, spurious activation of the naïve cells is prevented and effector cells can respond quickly to infection. Using atomic force microscopy and confocal imaging, Thauland et al. showed that naïve cells are stiffer than effector cells. Thus, the naïve cells made smaller and less involved contact regions with antigen-presenting cells. The decreased flexibility of the naïve cells resulted from diminished cofilin-mediated remodeling of the actin cytoskeleton. These findings show that mechanical properties of T cells govern their interactions with antigen-presenting cells and suggest that pharmacological modulation of T cell stiffness could change the threshold for activation.
Abstract
The factors that govern T cell activation control the initiation and progression of adaptive immune responses. T cells recognize their cognate antigen on the surface of antigen-presenting cells (APCs) through the T cell receptor, which results in the formation of a contact region (immune synapse) between the two cells and the activation of the T cells. Activated T cells proliferate and differentiate into effector T cells that secrete cytokines, provide help to B cells, and kill target cells. We asked whether the actin cytoskeleton governs differences in signaling in effector T cells versus naïve (unstimulated) T cells. Using atomic force microscopy and quantitative confocal microscopy, we found that naïve T cells had a mechanically stiffer cortical cytoskeleton than that of effector cells, which resulted in naïve cells forming smaller immune synapses with APCs. This suggests that the cytoskeletal stiffness of the T cell before it undergoes antigen stimulation predicts its subsequent dynamic engagement with APCs and its activation potential. Cytoskeletal rigidity depended on the activity of the actin-severing enzyme cofilin through a pathway requiring the small guanosine triphosphatase RhoA and the kinases ROCK (Rho-activated kinase) and LIMK. These findings suggest that the baseline cytoskeletal state controls T cell responses and that the underlying pathway could be a therapeutic target for modulating adaptive immunity.
