Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Sagi, Yoav; Landrigan, Angela; Levy, Ronald; Levy, Shoshana

doi:10.1073/pnas.1121307109

Cited by 32 publications

(22 citation statements)

References 65 publications

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“…In our work, we have stimulated CD81-silenced T cells through antigen presentation by APCs by using two different conjugation systems (Raji/SEE and Hom2/HA cells), obtaining similar results with both. Moreover, in agreement with our results, CD81 Ϫ/Ϫ T cells do not develop Th2 responses when activated by antigen-presenting B cells, with reduced IL-4 production (79), and CD81 acts as a T cell-costimulatory molecule in human T cells (37,38,75).…”

Section: Discussionsupporting

confidence: 80%

“…CD81-silenced T cells display reduced MTOC translocation toward the IS, which is TCR dependent (72) and necessary for full T cell activation (73) but independent of actin polarization (74). CD81 silencing reduces TCR downstream signaling, decreasing CD3, ZAP-70, LAT, and ERK1/2 phosphorylation, in agreement with data showing that CD81 T cell costimulation activates TCR and ERK more strongly than does CD28 (75). Also, CD81-knocked-down T cells have reduced IL-2 secretion, which is dependent on ERK1/2 activation (76), and express lower levels of the T cell activation marker CD69.…”

Section: Discussionsupporting

confidence: 73%

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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: 80%

Section: Discussionsupporting

confidence: 73%

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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“…Antibody mediated stimulation of T lymphocytes indicates that CD81 is an in vitro co-stimulator of the TCR [24], [25], suggesting that co-engagement of CD81 with antigen receptors facilitates the reorganization of the membrane, thereby reducing the threshold of cell activation. In the current study, we explored whether CD81 cell surface expression levels affect TCR mediated stimulation.…”

Section: Discussionmentioning

confidence: 99%

Cd81 Interacts with the T Cell Receptor to Suppress Signaling

et al. 2012

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CD81 (TAPA-1) is a ubiquitously expressed tetraspanin protein identified as a component of the B lymphocyte receptor (BCR) and as a receptor for the Hepatitis C Virus. In an effort to identify trans-membrane proteins that interact with the T-cell antigen receptor (TCR), we performed a membrane yeast two hybrid screen and identified CD81 as an interactor of the CD3delta subunit of the TCR. We found that in the absence of CD81, in thymocytes from knockout mice, TCR engagement resulted in stronger signals. These results were recapitulated in T cell lines that express low levels of CD81 through shRNA mediated silencing. Increased signaling did not result from alterations in the levels of TCR on the surface of T lymphocytes. Although CD81 is not essential for normal T lymphocyte development, it plays an important role in regulating TCR and possibly pre-TCR signal transduction by controlling the strength of signaling. CD81 dependent alterations in thymocyte signaling are evident in increased CD5 expression on CD81 deficient double positive (DP) thymocytes. We conclude that CD81 interacts with the T cell receptor to suppress signaling.

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“…• Metastasis suppressor in prostate cancer (Dong et al, 1995). • Indirect regulation of proteolytic function of urokinase type plasminogen uPA/uPAR system that possibly control cell motility and adhesion (Bass et al, 2005) • Regulatory role on the cell-surface expression and function of MT1-MMP (Schroder et al, 2013) Most cells, including lymphoid cells (Oren et al, 1990;Berditchevski et al, 1996;Levy et al, 1998;Berditchevski, 2001;Hemler, 2005) • Role in the regulation of lymphoma cell growth (Boismenu et al, 1996;Sagi et al, 2012). • HCV viral receptor (Pileri et al, 1998).…”

Section: Rom1mentioning

confidence: 99%

Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies

Detchokul

Williams

Parker

et al. 2014

British J Pharmacology

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One of the hallmarks of cancer is the ability to activate invasion and metastasis. Cancer morbidity and mortality are largely related to the spread of the primary, localized tumour to adjacent and distant sites. Appropriate management and treatment decisions based on predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are components of metastasis that are common to all primary tumours: dissociation from the primary tumour mass, reorganization/remodelling of extracellular matrix, cell migration, recognition and movement through endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma. One of the key and initial events is the increased ability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanin family of proteins play important roles in regulation of cancer cell migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, the tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis.

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Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81

Cited by 32 publications

References 65 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

Cd81 Interacts with the T Cell Receptor to Suppress Signaling

Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies

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