Role of ICAM-3 in the initial interaction of T lymphocytes and APCs

Montoya, Marı́a C.; Sancho, David; Bonello, G.; Collette, Yves; Langlet, Claire; He, Hai-Tao; Aparicio, Pedro; Alcover, Andrés; Olive, Daniel; Sánchez-Madrid, Francisco

doi:10.1038/ni753

Cited by 149 publications

(179 citation statements)

References 49 publications

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“…To evaluate the PKD1 effect on polarized exosome secretion in an IS model, we challenged GFP-CD63-expressing Jurkat cells with Staphylococcus enterotoxin E (SEE)-presenting Raji B cells, 35 which allowed analysis of GFP-CD63 + MVB traffic and exosome secretion. 9 2 cells were co-transfected with DsRed2-CD63 and the constructs GFP-PKD1WT, GFP-PKD1KD (kinase-dead) or GFP-PKD1CA (constitutively active).…”

Section: Resultsmentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

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Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase α (DGKα) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKα regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKα effect on MVB secretory traffic. Exosomes are nanovesicles that form as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs) and are then secreted by numerous cell types. 1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.Exosomes participate in many biological processes related to T-cell receptor (TCR)-triggered immune responses, including T lymphocyte-mediated cytotoxicity and activationinduced cell death (AICD), antigen presentation and intercellular miRNA exchange. [10][11][12][13][14][15] The discovery of exosome involvement in these responses increased interest in the regulation of exosome biogenesis and secretory traffic, with special attention to the contribution of lipids such as ceramide and DAG, as well as DAG-binding proteins. 14,16-21 These studies suggest that positive and negative DAG regulators may control secretory traffic. By transforming DAG into phosphatidic acid (PA), diacylglycerol kinase α (DGKα) is essential for the negative control of DAG function in T lymphocytes. 22 DGKα translocates transiently to the T-cell membrane after human muscarinic type 1 receptor (HM1R) triggering or to the immune synapse (IS) after TCR stimulation; at these subcellular locations, DGKα acts as a negative modulator of phospholipase C (PLC)-generated DAG. 23,24 The secretory vesicle pathway involves several DAGc...

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Section: Resultsmentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

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“…Notably, TCR engagement drives the transport of gangliosides and Lck (which is known to associate with hDlg) (47) from an intracellular store to the plasma membrane and the translocation of Lck-associated PKC to rafts at the immunological synapse. Of interest, ICAM-3 that accumulated in the uropod of polarized T cells after delivery by binding to the FERM domain of moesin (34) is subsequently targeted to sites of immune cell-cell contact by an unknown mechanism (10). The similarities between the FERM domains among 4.1 superfamily members might allow ICAM-3 at the uropod to interact with 4.1G for transport back to the leading edge.…”

Section: Discussionmentioning

confidence: 99%

“…Both of these essential components are influenced by receptor engagement at the synapse, and, in turn, both orchestrate molecular distribution and signal transduction during the interaction (7)(8)(9)). An initiating event in synapse formation may be the migration of intercellular adhesion molecule 3 (ICAM-3) to sites of cell-cell contact with the APC, where it engages its counter receptor as part of the "scanning" process (10). Engagement of ICAM-3 results in an increase in intracellular calcium concentration, the activation of tyrosine kinases, and activation of the integrin LFA-1 (10,11).…”

mentioning

confidence: 99%

“…An initiating event in synapse formation may be the migration of intercellular adhesion molecule 3 (ICAM-3) to sites of cell-cell contact with the APC, where it engages its counter receptor as part of the "scanning" process (10). Engagement of ICAM-3 results in an increase in intracellular calcium concentration, the activation of tyrosine kinases, and activation of the integrin LFA-1 (10,11). The mechanisms involved in such "inside-out" activation of leukocyte integrins are complex and not fully understood (12,13), but changes in avidity and affinity of LFA-1 involve clustering in membrane rafts (14 -16) and remodeling of the actin (9,17) and microtubule (18,19) cytoskeleton.…”

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confidence: 99%

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The LFA-1-associated Molecule PTA-1 (CD226) on T Cells Forms a Dynamic Molecular Complex with Protein 4.1G and Human Discs Large

Ralston

Hird

Zhang

et al. 2004

Journal of Biological Chemistry

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Clustering of the T cell integrin, LFA-1, at specialized regions of intercellular contact initiates integrin-mediated adhesion and downstream signaling, events that are necessary for a successful immunological response. But how clustering is achieved and sustained is not known. Here we establish that an LFA-1-associated molecule, PTA-1, is localized to membrane rafts and binds the carboxyl-terminal domain of isoforms of the actinbinding protein 4.1G. Protein 4.1 is known to associate with the membrane-associated guanylate kinase homologue, human discs large. We show that the carboxylterminal peptide of PTA-1 also can bind human discs large and that the presence or absence of this peptide greatly influences binding between PTA-1 and different isoforms of 4.1G. T cell stimulation with phorbol ester or PTA-1 cross-linking induces PTA-1 and 4.1G to associate tightly with the cytoskeleton, and the PTA-1 from such activated cells now can bind to the amino-terminal region of 4.1G. We propose that these dynamic associations provide the structural basis for a regulated molecular adhesive complex that serves to cluster and transport LFA-1 and associated molecules.

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“…Jurkat T cells bearing the TCR Vb8 chain recognize the staphylococcal enterotoxin E (SEE) superantigen bound to MHC class II in Raji APCs (Montoya et al, 2002). Upon stimulation of Jurkat T cells with SEE-loaded APCs, endogenous T cell clathrin relocalized and accumulated at the IS, as revealed by immunofluorescence using antibodies against the clathrin heavy chain (Fig.…”

Section: Clathrin Polarizes Towards the Immunological Synapsementioning

confidence: 99%

Endosomal clathrin drives actin accumulation at the immunological synapse

Calabia-Linares

Robles‐Valero

Fuente

et al. 2011

Journal of Cell Science

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SummaryAntigen-specific cognate interaction of T lymphocytes with antigen-presenting cells (APCs) drives major morphological and functional changes in T cells, including actin rearrangements at the immune synapse (IS) formed at the cell-cell contact area. Here we show, using cell lines as well as primary cells, that clathrin, a protein involved in endocytic processes, drives actin accumulation at the IS. Clathrin is recruited towards the IS with parallel kinetics to that of actin. Knockdown of clathrin prevents accumulation of actin and proteins involved in actin polymerization, such as dynamin-2, the Arp2/3 complex and CD2AP at the IS. The clathrin pool involved in actin accumulation at the IS is linked to multivesicular bodies that polarize to the cell-cell contact zone, but not to plasma membrane or Golgi complex. These data underscore the role of clathrin as a platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs.

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Role of ICAM-3 in the initial interaction of T lymphocytes and APCs

Cited by 149 publications

References 49 publications

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

The LFA-1-associated Molecule PTA-1 (CD226) on T Cells Forms a Dynamic Molecular Complex with Protein 4.1G and Human Discs Large

Endosomal clathrin drives actin accumulation at the immunological synapse

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