Regulation of T-cell activation by the cytoskeleton

Billadeau, Daniel D.; Nolz, Jeffrey C.; Gomez, Timothy S.

doi:10.1038/nri2021

Cited by 339 publications

(375 citation statements)

References 118 publications

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“…T-cell synapses are accompanied by T-cell MTOC and Golgi apparatus polarization towards the APC 46 . Moreover, both helper T cells and cytotoxic T cells are highly motile, both in vitro and in vivo, and reduce their locomotion when encountering cognate APC 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

et al. 2015

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Mast cells are tissue-resident immune cells that play a key role in inflammation and allergy. Here we show that interaction of mast cells with antibody-targeted cells induces the polarized exocytosis of their granules resulting in a sustained exposure of effector enzymes, such as tryptase and chymase, at the cell-cell contact site. This previously unidentified mast cell effector mechanism, which we name the antibody-dependent degranulatory synapse (ADDS), is triggered by both IgE-and IgG-targeted cells. ADDSs take place within an area of cortical actin cytoskeleton clearance in the absence of microtubule organizing centre and Golgi apparatus repositioning towards the stimulating cell. Remarkably, IgG-mediated degranulatory synapses also occur upon contact with opsonized Toxoplasma gondii tachyzoites resulting in tryptase-dependent parasite death. Our results broaden current views of mast cell degranulation by revealing that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens for dedicated secretion and defence.

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Section: Discussionmentioning

confidence: 99%

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

et al. 2015

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“…TCR engagement by specific MHC-presented peptides launches highly dynamic and coordinated transport events that recruit specific factors to the IS and exclude others from it. This signal initiation triggers a broad cascade of downstream signaling that includes dynamic F-actin remodeling at the IS, tyrosine phosphorylation, and release of calcium flux, which are coordinated to trigger transcriptional profiles, including induced expression of the T cell survival cytokine IL-2 (2).…”

mentioning

confidence: 99%

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

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“…Cofilin, from a family of actin‐binding proteins, depolymerizes the minus end of filaments and reorganizes actin filaments 27, 28. Cofilin plays critical roles in immunological synapse formation by controlling actin reorganization 29.…”

Section: Discussionmentioning

confidence: 99%

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

et al. 2018

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SummaryThe p21‐activated kinase 2 (Pak2), an effector molecule of the Rho family GTPases Rac and Cdc42, regulates diverse functions of T cells. Previously, we showed that Pak2 is required for development and maturation of T cells in the thymus, including thymus‐derived regulatory T (Treg) cells. However, whether Pak2 is required for the functions of various subsets of peripheral T cells, such as naive CD4 and helper T‐cell subsets including Foxp3+ Treg cells, is unknown. To determine the role of Pak2 in CD4 T cells in the periphery, we generated inducible Pak2 knockout (KO) mice, in which Pak2 was deleted in CD4 T cells acutely by administration of tamoxifen. Temporal deletion of Pak2 greatly reduced the number of Foxp3+ Treg cells, while minimally affecting the homeostasis of naive CD4 T cells. Pak2 was required for proliferation and Foxp3 expression of Foxp3+ Treg cells upon T‐cell receptor and interleukin‐2 stimulation, differentiation of in vitro induced Treg cells, and activation of naive CD4 T cells. Together, Pak2 is essential in maintaining the peripheral Treg cell pool by providing proliferation and maintenance signals to Foxp3+ Treg cells.

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Regulation of T-cell activation by the cytoskeleton

Cited by 339 publications

References 118 publications

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells

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Regulation of T-cell activation by the cytoskeleton

Cited by 339 publications

References 118 publications

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3+ regulatory T cells

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P21‐activated kinase 2 is essential in maintenance of peripheral Foxp3⁺ regulatory T cells