Characterization of dynamic actin associations with T-cell receptor microclusters in primary T cells

Smoligovets, Alexander A.; Smith, Adam W.; Wu, Hung‐Jen; Petit, Rebecca S.; Groves, Jay T.

doi:10.1242/jcs.092825

Cited by 56 publications

(62 citation statements)

References 45 publications

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“…This suggests that the coupling between microclusters and actin is rather transientmultiple weak links form and break at different times to generate a frictional force between microclusters and actin. Two subsequent studies provided further support for the idea of the frictional coupling model and showed that actin itself slows down as it passes over mechanically trapped TCRs (Yu et al, 2010;Smoligovets et al, 2012).…”

Section: Actin In Microcluster Translocation and Spatial Organizationmentioning

confidence: 85%

Modulation of T cell signaling by the actin cytoskeleton

Smoligovets

Groves

2013

Journal of Cell Science

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SummaryThe actin cytoskeleton provides a dynamic framework to support membrane organization and cellular signaling events. The importance of actin in T cell function has long been recognized to go well beyond the maintenance of cell morphology and transport of proteins. Over the past several years, our understanding of actin in T cell activation has expanded tremendously, in part owing to the development of methods and techniques to probe the complex interplay between actin and T cell signaling. On the one hand, biochemical methods have led to the identification of many key cytoskeleton regulators and new signaling pathways, whereas, on the other, the combination of advanced imaging techniques and physical characterization tools has allowed the spatiotemporal investigation of actin in T cell signaling. All those studies have made a profound impact on our understanding of the actin cytoskeleton in T cell activation. Many previous reviews have focused on the biochemical aspects of the actin cytoskeleton. However, here we will summarize recent studies from a biophysical perspective to explain the mechanistic role of actin in modulating T cell activation. We will discuss how actin modulates T cell activation on multiple time and length scales. Specifically, we will reveal the distinct roles of the actin filaments in facilitating TCR triggering, orchestrating 'signalosome' assembly and transport, and establishing protein spatial organization in the immunological synapse.

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Section: Actin In Microcluster Translocation and Spatial Organizationmentioning

confidence: 85%

Modulation of T cell signaling by the actin cytoskeleton

Smoligovets

Groves

2013

Journal of Cell Science

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“…1, 2, and 4), suggesting weaker interactions between these assemblies and the cell cytoskeleton. Studies following retrograde flow in the IS support this scenario, as the speed of TCR microcluster transport on supported lipid bilayers is about half the actin flow speed, and restriction of microcluster transport slows but does not stop actin retrograde flow (39)(40)(41). Moreover, immobilization of integrin receptors within the IS slows actin transport to a larger degree than TCR microclusters (39).…”

Section: Discussionmentioning

confidence: 99%

CD28 and CD3 have complementary roles in T-cell traction forces

Bashour¹,

Gondarenko

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

218

251

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Mechanical forces have key roles in regulating activation of T cells and coordination of the adaptive immune response. A recent example is the ability of T cells to sense the rigidity of an underlying substrate through the T-cell receptor (TCR) coreceptor CD3 and CD28, a costimulation signal essential for cell activation. In this report, we show that these two receptor systems provide complementary functions in regulating the cellular forces needed to test the mechanical properties of the extracellular environment. Traction force microscopy was carried out on primary human cells interacting with micrometer-scale elastomer pillar arrays presenting activation antibodies to CD3 and/or CD28. T cells generated traction forces of 100 pN on arrays with both antibodies. By providing one antibody or the other in solution instead of on the pillars, we show that force generation is associated with CD3 and the TCR complex. Engagement of CD28 increases traction forces associated with CD3 through the signaling pathway involving PI3K, rather than providing additional coupling between the cell and surface. Force generation is concentrated to the cell periphery and associated with molecular complexes containing phosphorylated Pyk2, suggesting that T cells use processes that share features with integrin signaling in force generation. Finally, the ability of T cells to apply forces through the TCR itself, rather than the CD3 coreceptor, was tested. Mouse cells expressing the 5C.C7 TCR exerted traction forces on pillars presenting peptide-loaded MHCs that were similar to those with α-CD3, suggesting that forces are applied to antigen-presenting cells during activation.T -cell activation is a key regulatory point of the adaptive immune response. It is initiated by recognition of peptideloaded MHCs (pMHCs) on antigen-presenting cells (APCs) by T-cell receptors (TCRs). Engagement of additional receptors on the T-cell surface leads to formation of a specialized interface termed the immune synapse (IS), which focuses communication between these cells. The IS has emerged as a compelling model of juxtacrine signaling, providing key insights into how the dynamics of such interfaces influence cell-cell communication. Mechanical forces originating from a range of sources, including cytoskeletal dynamics, also play important roles in T-cell activation. The initial spreading of T cells following contact with an activating surface is dependent on a burst of actin polymerization (1, 2). Subsequent retrograde flow of actin and contraction of actomyosin structures drive microscale reorganization of signaling complexes within this interface, resulting in formation of concentric central, peripheral, and distal supramolecular activation cluster (cSMAC, pSMAC, and dSMAC) structures that comprise the archetypal IS (3-8). The TCR complex itself may be triggered by external forces (9, 10), whereas TCR ligation may induce actin polymerization and generation of protrusive forces (11).More recently, mechanosensing by T cells was demonstrated in the context ...

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“…Nanopatterned substrates have been successfully employed to elucidate the role of receptor clustering in a number of cellular signaling systems, including T-cell activation, EphA2 receptor tyrosine kinase signaling, and integrin adhesion (24)(25)(26)(60)(61)(62)(63)(64)(65)(66). Unlike genetic or pharmacological perturbations that may have offtarget or deleterious effects (e.g., on protein stability), these nanopatterned substrates allow receptor clustering to be perturbed in a purely physical way, thereby avoiding such effects.…”

Section: Discussionmentioning

confidence: 99%

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

Biswas

Hartman

Zaidel-Bar

et al. 2016

Biophysical Journal

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Mechanotransduction at E-cadherin junctions has been postulated to be mediated in part by a force-dependent conformational activation of a-catenin. Activation of a-catenin allows it to interact with vinculin in addition to F-actin, resulting in a strengthening of junctions. Here, using E-cadherin adhesions reconstituted on synthetic, nanopatterned membranes, we show that activation of a-catenin is dependent on E-cadherin clustering, and is sustained in the absence of mechanical force or association with F-actin or vinculin. Adhesions were formed by filopodia-mediated nucleation and micron-scale assembly of E-cadherin clusters, which could be distinguished as either peripheral or central assemblies depending on their relative location at the cell-bilayer adhesion. Whereas F-actin, vinculin, and phosphorylated myosin light chain associated only with the peripheral assemblies, activated a-catenin was present in both peripheral and central assemblies, and persisted in the central assemblies in the absence of actomyosin tension. Impeding filopodia-mediated nucleation and micron-scale assembly of E-cadherin adhesion complexes by confining the movement of bilayer-bound E-cadherin on nanopatterned substrates reduced the levels of activated a-catenin. Taken together, these results indicate that although the initial activation of a-catenin requires micron-scale clustering that may allow the development of mechanical forces, sustained force is not required for maintaining a-catenin in the active state.

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Characterization of dynamic actin associations with T-cell receptor microclusters in primary T cells

Cited by 56 publications

References 45 publications

Modulation of T cell signaling by the actin cytoskeleton

Modulation of T cell signaling by the actin cytoskeleton

CD28 and CD3 have complementary roles in T-cell traction forces

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

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