Abstract
Ultrasensitivity allows filtering weak activating signals and responding emphatically to small changes in stronger stimuli. In the presence of positive feedback loops, ultrasensitivity enables the existence of bistability, which convert graded stimuli into switch-like, sometimes irreversible, responses. In this perspective, we discuss mechanisms that can potentially generate a bistable response in the phosphorylation/dephosphorylation monocycle that regulates the activity of cofilin in dynamic actin networks. We pay particular attention to the phosphatase Slingshot-1 (SSH-1), which is involved in a reciprocal regulation and a positive feedback loop for cofilin activation. Based on these signaling properties and experimental evidences, we propose that bistability in the cofilin signaling module might be instrumental in T cell responses to antigenic stimulation. Initially, a switch-like response in the amount of active cofilin as a function of SSH-1 activation might assist in controlling the naïve T cell specificity and sensitivity. Second, high concentrations of active cofilin might endow antigen-experienced T cells with faster and more efficient responses. We discuss the cofilin function in the context of T cell receptor triggering and spatial regulation of plasma membrane signaling molecules.
Highlights
Ultrasensitivity allows filtering weak activating signals and responding emphatically to small changes in stronger stimuli
Based on these signaling properties and experimental evidences, we propose that bistability in the cofilin signaling module might be instrumental in T cell responses to antigenic stimulation
Initial signaling events triggered by the T cell receptor (TCR) after the specific engagement of antigenic peptide–MHC complexes occur in dynamic TCR microclusters organized at the periphery of the immunological synapse (IS) [1]
Summary
Initial signaling events triggered by the T cell receptor (TCR) after the specific engagement of antigenic peptide–MHC complexes (pMHC) occur in dynamic TCR microclusters organized at the periphery of the immunological synapse (IS) [1]. The actin cytoskeleton was proved to promote a high dissociation rate These data pose the question about how brief TCR interactions can efficiently activate T cells that are scanning antigen-presenting cells (APCs), which frequently contain low densities of surface antigenic pMHC compared with endogenous pMHC. Antigenexperienced (Ag-e) T cells exhibit bigger TCR nanoclusters that parallel a lower activation threshold than the observed in naïve T cells [10] It seems that an avidity-maturation process mediates enhanced responses seen in effector or memory T cells [10, 11]. In addition to controlling kinetic parameters of the TCR/pMHC engagement and the molecular dynamics during early T cell activation, actin dynamics might be involved in the spatial and temporal organization of cell surface oligomers of signaling molecules
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