Mechanosensing in T Lymphocyte Activation

Judokusumo, Edward; Tabdanov, Erdem D.; Kumari, Sudha; Dustin, Michael L.; Kam, Lance C.

doi:10.1016/j.bpj.2011.12.011

Cited by 242 publications

(306 citation statements)

References 12 publications

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“…Our observation in this study mirrors the findings of a recent study by Kam and colleagues (20), who investigated the mechanosensing features of T lymphocyte cells. Their studies demonstrated that within a stiffness range between 10 and 100 kPa, the activation of T cells was obviously enhanced upon increasing substrate stiffness, as quantified by IL-2 secretion and phosphorylated Src family kinases and ZAP70 recruitment to the immunological synapse.…”

Section: Discussionsupporting

confidence: 91%

“…Based on this information, it is reasonable to speculate that the BCR might have mechanosensing ability toward the substrate presenting the Ags that may allow it to regulate these molecular events in the cascades of B cell activation. This speculation is also supported by two recent reports on T cell mechanosensing capability (20,21).…”

supporting

confidence: 77%

“…In this study, polyacrylamide gels with different Young's modulus were produced by using bisacrylamide concentrations of 0.8, 0.4, and 0.05% (w/v). Ags were tethered to the surface of polyacrylamide gel substrates following the methods described previously (20). In this study, streptavidin-conjugated acrylamide was polymerized into the polyacrylamide gel for the purpose of tethering the biotinylated F(ab9) 2 anti-IgM Ab as surrogate Ag, which was generally incubated with the substrate at 37˚C for 30 min at a concentration of 30 mg/ml.…”

Section: Preparation Of Polyacrylamide Gel Substrates For Tethering Agsmentioning

confidence: 99%

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B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

109

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B lymphocytes are activated upon Ag sensing by BCRs. The substrate presenting the Ag can show different degrees of stiffness. It is not clear whether B cells can respond to changes in substrate stiffness. In this study we use high-resolution, high-speed live cell imaging techniques to capture the molecular events in B cell activation after the recognition of Ags tethered to polyacrylamide gel substrates with variable degrees of stiffness as quantified by Young’s modulus (2.6–22.1 kPa). We show that the initiation of B cell activation is extremely sensitive to substrate stiffness. B cells exhibit much stronger activation responses when encountering Ags tethered to substrates with a high degree of stiffness as measured by the accumulation of BCR, phospho-spleen tyrosine kinase, and phosphotyrosine molecules into the B cell immunological synapse. Ags tethered to stiff substrates induce the formation of more prominent BCR and phospho-spleen tyrosine kinase microclusters with significantly enhanced colocalization as compared with Ags tethered to soft substrates. Moreover, the expression of the B cell activation marker CD69 is enhanced in B cells encountering Ags on stiffer substrates. Through time-lapse live cell imaging, we find that the different responses of B cells to substrate stiffness are only demonstrated 5 min after BCR and Ag recognition. Using a series of cytoskeleton inhibitors, we determine that the mechanosensing ability of B cells is dependent on microtubules, and only mildly linked to the actin cytoskeleton. These results suggest the importance of the mechanical properties mediated by substrate stiffness in B cell activation.

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Section: Discussionsupporting

confidence: 91%

supporting

confidence: 77%

Section: Preparation Of Polyacrylamide Gel Substrates For Tethering Agsmentioning

confidence: 99%

See 1 more Smart Citation

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

109

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“…Both mechanisms are likely to be physiologically relevant, because the effects of ROCK and MT inhibition on the pMLC are observed in both Jurkat and primary human CD4 + cells. How T cells use and modulate this pathway to achieve mechanosensing (76), as in the case of mesenchymal stem cells, remains to be understood. Interestingly, the lymph node itself is also mechanically active, because Rho inactivation in fibroblastic reticular cells enables lymph node expansion during inflammation (77).…”

Section: Discussionmentioning

confidence: 99%

Dynamic microtubules regulate cellular contractility during T-cell activation

Hui

Upadhyaya

2017

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

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T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell-substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.T lymphocytes, central players in the adaptive immune response, are activated when T-cell receptors (TCRs) on their surface recognize cognate peptide-major histocompatibility complex (pMHC) expressed on the surface of antigen-presenting cells (APCs). A burst of actin polymerization is triggered upon TCR stimulation (1), leading to an enhancement of the cell/APC contact area as the T cell spreads over the surface of the APC (2) and the formation of a macromolecular protein assembly known as the immunological synapse (IS) (3, 4). Accompanying IS formation, T cells also undergo a rapid polarization of the microtubule (MT) cytoskeleton, within 1-2 min after initial contact, that facilitates directional secretion of cytokines and cytolytic factors toward the APC (5-7). Therefore, the contact zone between T cells and APCs is a site at which the MT and actin cytoskeletons could potentially interact to regulate signaling.Recent studies have established that T cells generate significant traction stresses at the cell-cell interface, albeit relatively weak compared with adherent cells (8-11). These forces, which peak 5-10 min after stimulation, facilitate T-cell activation, in part, by inducing conformational changes in the TCR-CD3 complex (12-15). Although actin polymerization/depolymerization dynamics are essential for T cells to maintain dynamic traction stresses and to drive calcium influx and integrin affinity maturation (9, 16, 17), the regulatory pathways that control these cytoskeletal forces are not completely understood. In particular, whether and how the polarized MT cytoskeleton interacts with the actin cytoskeleton and regulates force generation at the T-cell-APC contact remain open questions.MTs in the cell exist in two populations: dynamic/tyrosinated MTs and stable MTs that have undergone posttranslational modifications, including detyrosination and acetylation (18). Previous studies of T-cell activation have elucidated that microtubuleorganizing center (MTOC) translocation is associated with the formati...

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“…Mutation of a Cys residue in the CD3ε stalk region to prevent the outside-in conformational transition leads to the blockade of αβ T cell development and impaired peripheral T cell function due to abnormal pre-TCR and TCR signaling [18,19,37]. Fourth, mechanical force has been shown to be critical for TCR signaling and might directly cause CD3 conformational change [2,[38][39][40][41][42][43][44]. These studies highlight the importance of conformational change in TCR triggering.…”

Section: Introductionmentioning

confidence: 93%

Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor

Guo

Yan

et al. 2017

Cell Res

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T-cell receptor-CD3 complex (TCR) is a versatile signaling machine that can initiate antigen-specific immune responses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain (CD3ε CD ). At the single-molecule level, we found that CD3ε CD could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3ε CD had heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3ε CD at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.

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Mechanosensing in T Lymphocyte Activation

Cited by 242 publications

References 12 publications

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Dynamic microtubules regulate cellular contractility during T-cell activation

Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor

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