Mediation of T-Cell Activation by Actin Meshworks

Beemiller, Peter; Krummel, Matthew F.

doi:10.1101/cshperspect.a002444

Cited by 57 publications

(58 citation statements)

References 82 publications

(77 reference statements)

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“…In this IS stage, slow protein dynamics and high levels of membrane protein-protein interactions suggest that IS protein enrichment is regulated by interactions within TEMs. Cytoskeleton polarization toward cell-cell contacts is crucial for the formation of the mature IS (56,57). Accordingly, treatment of J77 T cells with the actin-depolymerizing toxin latrunculin A before incubation with Raji/SEE cells prevented IS formation, with the very few T cell-B cell contacts observed being devoid of CD81-mCherry or endogenous CD3 accumulation at the IS (data not shown), in agreement with previous works (5,58).…”

Section: Discussionsupporting

confidence: 79%

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

Rocha-Perugini

Zamai

González-Granado

et al. 2013

Molecular and Cellular Biology

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In this study, we investigated the dynamics of the molecular interactions of tetraspanin CD81 in T lymphocytes, and we show that CD81 controls the organization of the immune synapse (IS) and T cell activation. Using quantitative microscopy, including fluorescence recovery after photobleaching (FRAP), phasor fluorescence lifetime imaging microscopy-Föster resonance energy transfer (phasorFLIM-FRET), and total internal reflection fluorescence microscopy (TIRFM), we demonstrate that CD81 interacts with ICAM-1 and CD3 during conjugation between T cells and antigen-presenting cells (APCs). CD81 and ICAM-1 exhibit distinct mobilities in central and peripheral areas of early and late T cell-APC contacts. Moreover, CD81-ICAM-1 and CD81-CD3 dynamic interactions increase over the time course of IS formation, as these molecules redistribute throughout the contact area. Therefore, CD81 associations unexpectedly define novel sequential steps of IS maturation. Our results indicate that CD81 controls the temporal progression of the IS and the permanence of CD3 in the membrane contact area, contributing to sustained T cell receptor (TCR)-CD3-mediated signaling. Accordingly, we find that CD81 is required for proper T cell activation, regulating CD3, ZAP-70, LAT, and extracellular signal-regulated kinase (ERK) phosphorylation; CD69 surface expression; and interleukin-2 (IL-2) secretion. Our data demonstrate the important role of CD81 in the molecular organization and dynamics of the IS architecture that sets the signaling threshold in T cell activation. The interaction between T lymphocytes and antigen-presenting cells (APCs) is essential for the initiation of the immune response. The dynamic structure formed at cell-to-cell contacts between T cells and APCs, called the immune synapse (IS), is characterized by controlled recruitment of membrane receptors to specific subcellular sites (1). Upon activation by an APC, T cell molecules involved in the IS redistribute in highly organized structures at the T cell-APC contact (2). The T cell receptor (TCR) and associated molecules concatenate into the central area (central supramolecular activation cluster [cSMAC]), whereas adhesion receptors rearrange in a surrounding external ring called the peripheral supramolecular activation cluster (pSMAC) (3). During IS formation, preclustered TCR "protein islands" converge into larger aggregates that translocate toward the cSMAC (4, 5), from where they are internalized and degraded (6). The balance between the generation and degradation of TCR microclusters is critical for sustained T cell activation (5, 7) and is modulated by ligand mobility (8). However, the mechanisms regulating protein receptor movement and the basis for IS molecular segregation are still poorly understood.A plethora of molecules are translocated to the IS during T cell activation (9). These include the tetraspanins CD81 (10) and CD82 (11), which are known to associate with several IS components such as major histocompatibility complex class II (MHCII) molecules, CD4, and LF...

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Section: Discussionsupporting

confidence: 79%

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

Rocha-Perugini

Zamai

González-Granado

et al. 2013

Molecular and Cellular Biology

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“…Ag presentation has to reach tremendous sensitivity with fast dynamics so that a TCR appropriately signals after encounter with a single peptide-MHC complex during scanning on an APC surface (56,57). For that purpose, signaling and adhesion receptors occur in preassembled protein islands or microdomains at the plasma membrane (1,2).…”

Section: Discussionmentioning

confidence: 99%

EWI-2 Association with α-Actinin Regulates T Cell Immune Synapses and HIV Viral Infection

Gordon-Alonso

Sala-Valdés

Rocha-Perugini

et al. 2012

The Journal of Immunology

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EWI motif-containing protein 2 (EWI-2) is a member of the Ig superfamily that links tetraspanin-enriched microdomains to the actin cytoskeleton. We found that EWI-2 colocalizes with CD3 and CD81 at the central supramolecular activation cluster of the T cell immune synapse. Silencing of the endogenous expression or overexpression of a cytoplasmic truncated mutant of EWI-2 in T cells increases IL-2 secretion upon Ag stimulation. Mass spectrometry experiments of pull-downs with the C-term intracellular domain of EWI-2 revealed the specific association of EWI-2 with the actin-binding protein α-actinin; this association was regulated by PIP2. α-Actinin regulates the immune synapse formation and is required for efficient T cell activation. We extended these observations to virological synapses induced by HIV and found that silencing of either EWI-2 or α-actinin-4 increased cell infectivity. Our data suggest that the EWI-2–α-actinin complex is involved in the regulation of the actin cytoskeleton at T cell immune and virological synapses, providing a link between membrane microdomains and the formation of polarized membrane structures involved in T cell recognition.

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“…121 It also participates actively in several processes in immune cells: migration, 122 phagocytosis, 9 immune synapsis and cell signaling. 123,124 Actin dynamics are critical for phagocytosis and endocytosis in a wide variety of cell types. Conveniently, several pathogens, through diverse mechanisms, manipulate the cytoskeleton to infect host cells.…”

Section: Resultsmentioning

confidence: 99%

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

2015

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Mediation of T-Cell Activation by Actin Meshworks

Cited by 57 publications

References 82 publications

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

EWI-2 Association with α-Actinin Regulates T Cell Immune Synapses and HIV Viral Infection

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

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