Cytoskeletal adaptivity regulates T cell receptor signaling

Thauland, Timothy J.; Hu, Kenneth H.; Bruce, Marc A.; Butte, Manish J.

doi:10.1126/scisignal.aah3737

Cited by 67 publications

(66 citation statements)

References 42 publications

(52 reference statements)

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“…These findings suggest that cellular deformability serves as an important characteristic in predicting T cell interactions with APCs and their subsequent activation. Consistent with our findings that actin organization and dynamics link macrophage mechanotype and function, the actin-severing factor cofilin was found to be critical for modulating T cell deformability and immune synapses with APCs (71). Actin remodeling is also critical for intracellular trafficking and receptor internalization and sensitization (72-74); in future research it will be important to determine how these cellular functions are regulated by signaling through b-AR.…”

Section: Discussionsupporting

confidence: 80%

Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Kim

Christodoulides

et al. 2018

FASEB j.

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Critical functions of immune cells require them to rapidly change their shape and generate forces in response to cues from their surrounding environment. However, little is known about how soluble factors that may be present in the microenvironment modulate key aspects of cellular mechanobiology—such as immune cell deformability and force generation—to impact functions such as phagocytosis and migration. Here we show that signaling by soluble stress hormones through β‐adrenoceptors (β‐AR) reduces the deformability of macrophages; this is dependent on changes in the organization of the actin cytoskeleton and is associated with functional changes in phagocytosis and migration. Pharmacologic interventions reveal that the impact of β‐AR signaling on macrophage deformability is dependent on actin‐related proteins 2/3, indicating that stress hormone signaling through β‐AR shifts actin organization to favor branched structures rather than linear unbranched actin filaments. These findings show that through remodeling of the actin cytoskeleton, β‐AR‐mediated stress hormone signaling modulates macrophage mechanotype to impact functions that play a critical role in immune response.—Kim, T.‐H., Ly, C., Christodoulides, A., Nowell, C. J., Gunning, P. W., Sloan, E. K., Rowat, A. C. Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function. FASEB J. 33, 3997–4006 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 80%

Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Kim

Christodoulides

et al. 2018

FASEB j.

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“…The size of the interface between T cells and antigen presenting cells ( Fig. 1D) varies based on cytoskeletal state of the T cell (Thauland et al, 2017), with most contacts falling in the range from 5-25 μm 2 . If one assumes an area of 10 μm 2 for a typical immune synapse, the large particles (2.25 μm radius) would offer a hemispheric area of ~32 μm, so an immune synapse sized 10 μm 2 would engage ~⅓ of the hemisphere and would engage ~26K antibodies (high density coating), 2660 antibodies (medium), and 330 molecules (low).…”

Section: Resultsmentioning

confidence: 99%

“…We showed in prior work that the size of the immune synapse in naive versus effector (recently activated) T cells controls the amount of signal they accumulate in their interactions with APCs (Thauland et al, 2017). We sought to test the coupling of signal accumulation and synapse size in a reductionist manner.…”

Section: T Cells Cytotoxic T Cells Have Important Applications In Enmentioning

confidence: 99%

“…These results show that the size of the immune synapse is larger when the cells are more activated. Our prior published result compared the size of the synapses for naïve T cells versus effector T cells (lymphoblasts in day 3-5 of culture) (Thauland et al, 2017), and showed that activation of cofilin in effector T cells enabled changes to the cytoskeleton that allowed for larger synapses and a lower threshold of activation than naïve T cells. In other words, that the threshold of activation was determined by the size of the synapse and thus the dynamic ability of the cytoskeleton to rearrange when in contact with an APC.…”

Section: T Cells Cytotoxic T Cells Have Important Applications In Enmentioning

confidence: 99%

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Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells

Majedi

Hasani-Sadrabadi

Thauland

et al. 2019

Preprint

Self Cite

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Activation of T cells by antigen presenting cells allows them to proliferate, produce cytokines, and kill infected or cancerous cells. We and others have shown that T cell receptors receive and in fact require mechanical forces from their own movements and the movements of antigen presenting cells. Emulation of T cell activation in vitro allows for the massive expansion of T cells necessary for clinical applications. In this paper, we studied the impact of augmenting novel artificial antigen presenting cells of various sizes and antigenic signal strength with mechanical, oscillatory movement. We showed that dynamic culture roughly doubles signal strength as compared to conventional, static culture. We demonstrated that tuning the strength of signal to a "sweet spot" allows for robust expansion of induced regulatory T cells, which is impeded by approaches that simply maximize activation.

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“…Because the actomyosin cytoskeleton is a major regulator of cortical stiffness (Thauland, Hu, Bruce, & Butte, 2017), we next sought to investigate cellular stiffness upon bacterial invasion. For this, we utilised microindentation, which served as a physical measurement reflecting cell cortical stiffness.…”

Section: Shigella Induces Cortical Stiffness Associated With Increamentioning

confidence: 99%

Shigellaimpairs human T lymphocyte responsiveness by hijacking actin cytoskeleton dynamics and T cell receptor vesicular trafficking

Samassa

Ferrari

Husson

et al. 2020

Cellular Microbiology

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Strategies employed by pathogenic enteric bacteria, such as Shigella, to subvert the host adaptive immunity are not well defined. Impairment of T lymphocyte chemotaxis by blockage of polarised edge formation has been reported upon Shigella infection. However, the functional impact of Shigella on T lymphocytes remains to be determined. Here, we show that Shigella modulates CD4+ T cell F‐actin dynamics and increases cell cortical stiffness. The scanning ability of T lymphocytes when encountering antigen‐presenting cells (APC) is subsequently impaired resulting in decreased cell–cell contacts (or conjugates) between the two cell types, as compared with non‐infected T cells. In addition, the few conjugates established between the invaded T cells and APCs display no polarised delivery and accumulation of the T cell receptor to the contact zone characterising canonical immunological synapses. This is most likely due to the targeting of intracellular vesicular trafficking by the bacterial type III secretion system (T3SS) effectors IpaJ and VirA. The collective impact of these cellular reshapings by Shigella eventually results in T cell activation dampening. Altogether, these results highlight the combined action of T3SS effectors leading to T cell defects upon Shigella infection.

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Cytoskeletal adaptivity regulates T cell receptor signaling

Cited by 67 publications

References 42 publications

Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells

Shigellaimpairs human T lymphocyte responsiveness by hijacking actin cytoskeleton dynamics and T cell receptor vesicular trafficking

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