Biphasic response of T cell activation to substrate stiffness

Yuan, Dennis Jinglun; Shi, Lingting; Kam, Lance C.

doi:10.1016/j.biomaterials.2021.120797

Cited by 36 publications

(28 citation statements)

References 46 publications

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“…Many types of cells show greater dispersal and proliferation with increasing stiffness, and previous studies highlighted that the adhesive ligand density can also regulate the proliferation and function of cells. , We can also modify various functional motifs to improve the performance of FEFK in biomedical applications. Integrins are heterodimers and transmit signals by structurally connecting the cytoskeleton of immune cells with ECM.…”

Section: Resultsmentioning

confidence: 99%

Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy

Jie

Mao

Cao

et al. 2022

ACS Appl. Mater. Interfaces

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CAR-T-cell therapies must be expanded to obtain a large number of effector cells quickly, and the current technology cannot address this challenge. A longer operational time would lose or alter the function and phenotype of CAR-T cells in response to therapy, and it also causes a loss in the optimal treatment time for patients. At present, lower survival time and homing efficiency reduce the antitumor effect of CAR-T in vivo. But nobody has solved these two issues in one system, which has a similar microenvironment of lymphoid organs to activate/expand cell delivery for immunotherapy. Here, we generated artificial, customized immune cell matrix scaffolds based on a self-assembling peptide to preserve and augment the cell phenotype in light of the characteristics of CAR-T. The all-in-one nanoscale matrix scaffolds reduced the processing time of CAR-T to 3 days and resulted in over a 10-fold increase compared with the traditional protocol. The cells were combined to modulate mechanotransduction and chemical signals, and the mimic matrix scaffolds showed optimal stiffness and adhesive ligand density, thereby accelerating CAR-T-cell proliferation. Meanwhile, engineering CAR-T-secreted intrinsic PD-1 blocking single-chain variable fragments (scFv) further increased cell proliferation and cytotoxicity by resisting the self and tumor microenvironment in a paracrine and autocrine manner. Local delivery of CAR-T cells from the scaffolds significantly enabled long-term retention, suppressed tumor growth, and increased infiltration of effector T cells compared with traditional CAR-T treatment. The application of bioengineering and genetic engineering approaches has led to the development of rapid culture environments that can control matrix scaffold properties for CAR-T-cell and cancer immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy

Jie

Mao

Cao

et al. 2022

ACS Appl. Mater. Interfaces

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“…128 In a separate study, O'Connor et al found that soft nanoparticles (Young's modulus < 100 kPa) contributed to greater T cell activation and expansion. 129,130 The softer materials stimulated a greater amount of IL-2 secretion by CD4 + and CD8 + T cells, induced the differentiation of aggregated CD4 + T cells into Th1 cells, and promoted the release of the pro-inflammatory cytokine IFN-γ. 129 The surface morphology of NPs affects cellular biological responses by modifying the elasticity and shape of cells.…”

Section: Immunoregulatory Effects Of Nanoparticle Physical Characteri...mentioning

confidence: 99%

Immunomodulatory nanotherapeutic approaches for periodontal tissue regeneration

Xie

Ivanovski

et al. 2023

Nanoscale

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“…In the context of immunology, T cells, and the T cell receptors (TCRs), have a special significance in being the very first players in adaptive immunity. Mechanics of T cells has been studied using a variety of techniques [Saitakis et al, 2017], recently revealing that T cells have atypical mechanical responses [Wahl et al, 2019, Yuan et al, 2021]. Likewise, mechanics of the interaction of the TCR and its molecular partner, the peptide loaded Major Histocompatibility Complex (pMHC), is a subject of current research with some groups reporting a catch bond [Kim et al, 2009, Liu et al, 2014], and some others not [Limozin et al, 2019].…”

Section: Introductionmentioning

confidence: 99%

“…It is thus clear that force is an important control parameter of molecular function (especially in leukocytes). Interestingly, unlike in most other cell types, the sensing of mechanical environment in T cells appears to be myosin independent [Dillard et al, 2014, Wahl et al, 2019]; the extent of its spreading, when mediated by TCR alone, is biphasic with substrate stiffness [Wahl et al, 2019, Yuan et al, 2021]. T cells spread increasingly better on stiffer substrate, but only up to a point, after which the harder the substrate, the lesser the spreading [Judokusumo et al, 2012, O’Connor et al, 2012, Wahl et al, 2019, Yuan et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, unlike in most other cell types, the sensing of mechanical environment in T cells appears to be myosin independent [Dillard et al, 2014, Wahl et al, 2019]; the extent of its spreading, when mediated by TCR alone, is biphasic with substrate stiffness [Wahl et al, 2019, Yuan et al, 2021]. T cells spread increasingly better on stiffer substrate, but only up to a point, after which the harder the substrate, the lesser the spreading [Judokusumo et al, 2012, O’Connor et al, 2012, Wahl et al, 2019, Yuan et al, 2021]. Such a behavior can be a result of the TCR-ligand bond being a catch bond, as modelled in the context of early spreading of fibroblasts [Oakes et al, 2018], but it could also be explained by a model that considers the mechanics and kinetics of the entire molecular assembly that links the cytoskeleton to the substrate [Wahl et al, 2019].…”

Section: Introductionmentioning

confidence: 99%

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Probing mechanical interaction of immune receptors and cytoskeleton by membrane nanotube extraction

Manca

Eich

N'Dao

et al. 2022

Preprint

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The role of force application in immune cell recognition is now well established, the force being transmitted between the actin cytoskeleton to the anchoring ligands through receptors such as integrins. In this chain, the mechanics of the cytoskeleton to receptor link, though clearly crucial, remains poorly understood. To probe this link, we combine mechanical extraction of membrane tubes from T cells using optical tweezers, and fitting of the resulting force curves with a viscoelastic model taking into account the cell and relevant molecules. We find that it is possible to separate the cell-scale and molecular-scale effects and thus to estimate the stiffness of this putative link to be of the order of 0.05 pN/nm. We solicit this link using four different antibodies against various membrane bound receptors: antiCD3 to target the T Cell Receptor (TCR) complex, antiCD45 for the long sugar CD45, and two clones of antiCD11 targeting open or closed conformation of LFA1 integrins. Upon disruption of the cytoskeleton, the stiffness of the link changes for two of the receptors, exposing the existence of a receptor to cytoskeleton link - namely TCR-complex and open LFA1, and does not change for the other two where no such a link was expected. Our integrated approach allows us to probe, for the first time, the mechanics of the intracellular receptor-cytoskeleton link in immune cells. In doing so, we provide a quantitative value for the elasticity of the putative link, and elucidate a mechanism bridging molecular and cellular scales.

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Biphasic response of T cell activation to substrate stiffness

Cited by 36 publications

References 46 publications

Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy

Customized Multifunctional Peptide Hydrogel Scaffolds for CAR-T-Cell Rapid Proliferation and Solid Tumor Immunotherapy

Immunomodulatory nanotherapeutic approaches for periodontal tissue regeneration

Probing mechanical interaction of immune receptors and cytoskeleton by membrane nanotube extraction

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