Biphasic mechanosensitivity of TCR mediated adhesion of T lymphocytes

Wahl, Astrid Klopstad; Dinet, Céline; Dillard, Pierre; Puech, Pierre-Henri; Limozin, Laurent; Sengupta, Kheya

doi:10.1101/232041

Cited by 3 publications

(4 citation statements)

References 29 publications

(35 reference statements)

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“…A special advantage of the bilayer approach is that the bilayers can be easily and systematically functionalized by attaching the soluble extracellular regions of receptor ligands and other components of the membrane, allowing quantitative analysis of T cell responses. In recent years, however, it has become apparent that T cell behavior is also affected by the mechanical properties of surfaces they encounter ( 4 , 5 , 6 , 7 , 8 , 9 ), and glass is 10 7 - to 10 8 -fold stiffer than eukaryotic cells ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…It might have been expected that lymphocytes would constitute a special case of mechanosensitive cells because they traverse great distances across multiple organs and tissues in the course of interrogating other cells for signs of infection and malaise. Accordingly, multiple groups have shown that lymphocytes, i.e., both T cells ( 4 , 6 ) and B cells ( 11 , 12 ), are affected by surface mechanical properties. For example, T cells interacting with elastomer micropillar arrays undergo cytoskeletal changes and intracellular signaling responses that vary with pillar length and flexibility ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions

Lippert

Dimov

Winkel

et al. 2021

Biophysical Journal

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Much of what we know about the early stages of T cell activation has been obtained from studies of T cells interacting with glass-supported lipid bilayers that favor imaging but are orders of magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing ''soft bilayers'' with physiological levels of mechanical resistance (Young's modulus of 4 kPa). Comparisons of T cell behavior on soft and glass-supported bilayers revealed that whereas late stages of T cell activation are thought to be substrate-stiffness dependent, early calcium signaling was unaffected by substrate rigidity, implying that early steps in T cell receptor triggering are not mechanosensitive. The exclusion of large receptor-type phosphatases was observed on the soft bilayers, however, even though it is yet to be demonstrated at authentic cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions

Lippert

Dimov

Winkel

et al. 2021

Biophysical Journal

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“…Varying degrees of stiffness can alter the morphology of T cells and their activation or proliferation rates (Judokusumo et al, 2012;Saitakis et al, 2017). T cell activation involving CD3 and CD28, which are non-integrin glycoprotein receptors mediating T cell activation, or the ligation of leukocyte function-associated antigen-1 (LFA-1,α L β 2 ) integrins, are often reported to be mechanosensitive processes, affecting proliferation and chemokine production (O'Connor et al, 2012;Bashoura et al, 2014;Basu et al, 2016;Hickey et al, 2019;Wahl et al, 2019;.…”

Section: Introductionmentioning

confidence: 99%

Integrin cross-talk modulates stiffness-independent motility of CD4+ T lymphocytes

Kim

Hammer

2021

MBoC

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To carry out their physiological responsibilities, CD4+ T lymphocytes interact with various tissues of different mechanical properties. Recent studies suggest that T cells migrate upstream on surfaces expressing ICAM-1 through interaction with LFA-1 integrins. LFA-1 likely interacts as a mechanosensor, and thus we hypothesized that substrate mechanics might affect the ability of LFA-1 to support upstream migration of T cells under flow. Here, we measured motility of CD4+ T lymphocytes on polyacrylamide gels with pre-determined stiffnesses containing ICAM-1, VCAM-1, or 1:1 mixture of VCAM-1/ICAM-1. Under static conditions, we found that CD4+ T cells exhibit an increase in motility on ICAM-1, but not on VCAM-1 or VCAM-1/ICAM-1 mixed, surfaces as a function of matrix stiffness. The mechanosensitivity of T cell motility on ICAM-1 is overcome when VLA-4 is ligated with soluble VCAM-1. Lastly, we observed that CD4+ T cells migrate upstream under flow on ICAM-1-functionalized hydrogels, independent of substrate stiffness. In summary, we show that CD4+ T cells under no flow respond to matrix stiffness through LFA-1, and that the crosstalk of VLA-4 and LFA-1 can compensate for deformable substrates. Interestingly, CD4+ T lymphocytes migrated upstream on ICAM-1 regardless of the substrate stiffness, suggesting that flow can compensate for substrate stiffness.

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“…Accordingly, multiple groups have shown that lymphocytes, i.e. both T cells 2,3 and B cells 4,5 are affected by surface mechanical properties. For example, T cells interacting with elastomer micropillar arrays undergo cytoskeletal changes and intracellular signaling responses that vary with pillar length and flexibility 6 .…”

Section: Introductionmentioning

confidence: 99%

Robust T-cell signaling triggered on soft polydimethylsiloxane-supported lipid-bilayers

Lippert

Dimov

Winkel

et al. 2020

Preprint

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12The T-cell receptor (TCR) is thought to be triggered either by mechano-transduction or local tyrosine 13 phosphatase exclusion at cell-cell contacts. However, the effects of the mechanical properties of 14 activating surfaces have only been tested for late-stage T-cell activation, and phosphatase segregation 15 has mostly been studied on glass-supported lipid bilayers that favor imaging but are orders-of-16 magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to 17 polydimethylsiloxane polymer supports, producing 'soft bilayers' with physiological levels of 18 mechanical resistance (Young's modulus of 4 kPa). Comparisons of T-cell behavior on soft and glass-19 supported bilayers revealed that early calcium signaling is unaffected by substrate rigidity, implying 20 that early steps in TCR triggering are not mechanosensitive. Robust phosphatase exclusion was 21 observed on the soft bilayers, however, suggesting it likely occurs at cell-cell contacts. This work sets 22 the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking 23 physiological cell-cell contact. 24 25

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Biphasic mechanosensitivity of TCR mediated adhesion of T lymphocytes

Cited by 3 publications

References 29 publications

Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions

Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions

Integrin cross-talk modulates stiffness-independent motility of CD4+ T lymphocytes

Robust T-cell signaling triggered on soft polydimethylsiloxane-supported lipid-bilayers

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