CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration

Quast, Thomas; Eppler, Felix J.; Semmling, Verena; Schild, Cora; Homsi, Yahya; Levy, Shoshana; Lang, Thorsten; Kurts, Christian; Kolanus, Waldemar

doi:10.1182/blood-2010-12-326595

Cited by 63 publications

(72 citation statements)

References 48 publications

(62 reference statements)

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“…5K). CD37 ablation induces in DCs a similar phenotype to that observed when the tetraspanin CD81 has been knocked down through inhibitory RNA (46). Both CD37 2/2 and CD81 kd DCs are poor migrators in two dimensions and have a similar inability to form membrane protrusions and activate Rac; indeed, a direct molecular interaction between Rac and CD81 has been reported (11).…”

Section: /2mentioning

confidence: 86%

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37

Jones

Wee

Demaria

et al. 2016

The Journal of Immunology

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This study supports a new concept where the opposing functions of the tetraspanins CD37 and CD82 may coordinate changes in migration and Ag presentation during dendritic cell (DC) activation. We have previously published that CD37 is downregulated upon monocyte-derived DC activation, promotes migration of both skin and bone marrow–derived dendritic cells (BMDCs), and restrains Ag presentation in splenic and BMDCs. In this article, we show that CD82, the closest phylogenetic relative to CD37, appears to have opposing functions. CD82 is upregulated upon activation of BMDCs and monocyte-derived DCs, restrains migration of skin and BMDCs, supports MHC class II maturation, and promotes stable interactions between T cells and splenic DCs or BMDCs. The underlying mechanism involves the rearrangement of the cytoskeleton via a differential activation of small GTPases. Both CD37−/− and CD82−/− BMDCs lack cellular projections, but where CD37−/− BMDCs spread poorly on fibronectin, CD82−/− BMDCs are large and spread to a greater extent than wild-type BMDCs. At the molecular level, CD82 is a negative regulator of RhoA, whereas CD37 promotes activation of Rac-1; both tetraspanins negatively regulate Cdc42. Thus, this study identifies a key aspect of DC biology: an unactivated BMDC is CD37hiCD82lo, resulting in a highly motile cell with a limited ability to activate naive T cells. By contrast, a late activated BMDC is CD37loCD82hi, and thus has modified its migratory, cytoskeletal, and Ag presentation machinery to become a cell superbly adapted to activating naive T cells.

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Section: /2mentioning

confidence: 86%

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37

Jones

Wee

Demaria

et al. 2016

The Journal of Immunology

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“…CD81 is connected to the actin cytoskeleton through its association with ezrin-radixin-moesin (ERM) proteins (67), which are recruited to the IS and play a role in T cell activation (68). F-actin dynamics is also regulated by Rho GTPases (69), and CD81 was recently shown to associate directly with the small GTPase Rac-1 (70,71). However, our data for CD81 C-terminal cell-permeable peptides and soluble GST-LEL-CD81 fusion proteins suggest that the role of CD81 as an IS organizer might be related to its ability to interact with other transmembrane proteins, regulating their diffusional properties and subcellular localization rather than direct signaling or anchoring to the cytoskeleton through its C-terminal domain.…”

Section: Discussionmentioning

confidence: 99%

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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“…Tetraspanins molecularly associate with integrins and regulate outside-in signaling and cytoskeletal rearrangement as evidenced by impaired adhesion strengthening under flow and cell spreading observed in tetraspanin-deficient cells [27][28][29][30][31]. To test if CD37 plays a similar role in DCs, we first measured DC adhesion to ECM substrates under low shear flow conditions.…”

Section: Adhesion and Cell Spreading Is Impaired In Cd37 −/− Dcsmentioning

confidence: 99%

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

et al. 2013

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Previous studies on the role of the tetraspanin CD37 in cellular immunity appear contradictory. In vitro approaches indicate a negative regulatory role, whereas in vivo studies suggest that CD37 is necessary for optimal cellular responses. To resolve this discrepancy, we studied the adaptive cellular immune responses of CD37 −/− mice to intradermal challenge with either tumors or model antigens and found that CD37 is essential for optimal cell-mediated immunity. We provide evidence that an increased susceptibility to tumors observed in CD37 −/− mice coincides with a striking failure to induce antigenspecific IFN-γ-secreting T cells. We also show that CD37 ablation impairs several aspects of DC function including: in vivo migration from skin to draining lymph nodes; chemotactic migration; integrin-mediated adhesion under flow; the ability to spread and form actin protrusions and in vivo priming of adoptively transferred naïve T cells. In addition, multiphoton microscopy-based assessment of dermal DC migration demonstrated a reduced rate of migration and increased randomness of DC migration in CD37 −/− mice.Together, these studies are consistent with a model in which the cellular defect that underlies poor cellular immune induction in CD37 −/− mice is impaired DC migration. Keywords: CD37 r Cellular immunity r Dendritic cells r Migration r TetraspaninsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdaptive cellular immunity is initiated by presentation of foreign antigen by DCs to antigen-specific naïve T lymphocytes. DCs exist sparsely in peripheral tissues in a state specialized for antigen uptake and processing. However, upon pathogen encounter, DCsCorrespondence: Dr. Mark D. Wright e-mail: Mark.Wright@monash.edu transduce signals through pattern recognition receptors, leading to an increased expression of cell surface molecules and cytokines, and induction of DC migration from the periphery to draining lymph nodes (DLNs) via afferent lymphatic vessels. Thus, upon their arrival in secondary lymphoid organs, DCs are equipped to initiate adaptive cellular immune responses through their ability to * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1208-1219 Cellular immune response 1209 activate naïve antigen-specific T cells [1]. Despite the importance of DC migration from the periphery to DLNs, the roles of the numerous molecules that regulate this process are incompletely understood. One such molecule is the leukocyte-specific membrane protein CD37, a member of the tetraspanin protein superfamily. Tetraspanins molecularly organize cellular membranes by interactions with partner molecules, which they direct into regulated signal-transducing tetraspanin-enriched microdomains. The cellular processes regulated by tetraspanin-mediated molecular organization include proliferation, adhesion and migration [2,3]. In immune cells, many important cell s...

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CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration

Cited by 63 publications

References 48 publications

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37

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

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

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