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Michael L Dustin - One of the best experts on this subject based on the ideXlab platform.
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the tyrosine phosphatase shp 1 promotes t cell adhesion by activating the adaptor protein crkii in the Immunological Synapse
Science Signaling, 2017Co-Authors: Inbar Azoulayalfaguter, Michael L Dustin, Marianne Strazza, Michael Peled, Hila Novak, James E MullerAbstract:The adaptor protein CrkII regulates T cell adhesion by recruiting the guanine nucleotide exchange factor C3G, an activator of Rap1. Subsequently, Rap1 stimulates the integrin LFA-1, which leads to T cell adhesion and interaction with antigen-presenting cells (APCs). The adhesion of T cells to APCs is critical for their proper function and education. The interface between the T cell and the APC is known as the Immunological Synapse. It is characterized by the specific organization of proteins that can be divided into central supramolecular activation clusters (c-SMACs) and peripheral SMACs (p-SMACs). Through total internal reflection fluorescence (TIRF) microscopy and experiments with supported lipid bilayers, we determined that activated Rap1 was recruited to the Immunological Synapse and localized to the p-SMAC. C3G and the active (dephosphorylated) form of CrkII also localized to the same compartment. In contrast, inactive (phosphorylated) CrkII was confined to the c-SMAC. Activation of CrkII and its subsequent movement from the c-SMAC to the p-SMAC depended on the phosphatase SHP-1, which acted downstream of the T cell receptor. In the p-SMAC, CrkII recruited C3G, which led to Rap1 activation and LFA-1–mediated adhesion of T cells to APCs. Functionally, SHP-1 was necessary for both the adhesion and migration of T cells. Together, these data highlight a signaling pathway in which SHP-1 acts through CrkII to reshape the pattern of Rap1 activation in the Immunological Synapse.
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Comprehensive Analysis of Immunological Synapse Phenotypes Using Supported Lipid Bilayers.
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Salvatore Valvo, Viveka Mayya, Elena Seraia, Jehan Afrose, Hila Novak-kotzer, Daniel Ebner, Michael L DustinAbstract:Supported lipid bilayers (SLB) formed on glass substrates have been a useful tool for study of immune cell signaling since the early 1980s. The mobility of lipid-anchored proteins in the system, first described for antibodies binding to synthetic phospholipid head groups, allows for the measurement of two-dimensional binding reactions and signaling processes in a single imaging plane over time or for fixed samples. The fragility of SLB and the challenges of building and validating individual substrates limit most experimenters to ~10 samples per day, perhaps increasing this few-fold when examining fixed samples. Successful experiments might then require further days to fully analyze. We present methods for automation of many steps in SLB formation, imaging in 96-well glass bottom plates, and analysis that enables >100-fold increase in throughput for fixed samples and wide-field fluorescence. This increased throughput will allow better coverage of relevant parameters and more comprehensive analysis of aspects of the Immunological Synapse that are well reconstituted by SLB.
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hiv envelope gp120 alters t cell receptor mobilization in the Immunological Synapse of uninfected cd4 t cells and augments t cell activation
Journal of Virology, 2016Co-Authors: Jing Deng, Michael L Dustin, Yuya Mitsuki, Guomiao Shen, Jocelyn C Ray, Claudia Cicala, James Arthos, Catarina E HioeAbstract:HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits Immunological Synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell Immunological Synapse affects Synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt Immunological Synapse formation. Instead, the HIV Env accumulated with TCR at the center of the Synapse, altered the kinetics of TCR recruitment to the Synapse and affected Synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the Synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the Immunological Synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells. IMPORTANCE There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called Immunological Synapse. We found that the HIV envelope is recruited to the center of the Immunological Synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal Immunological Synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.
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cd28 cd80 interactions control regulatory t cell motility and Immunological Synapse formation
Journal of Immunology, 2014Co-Authors: Timothy J Thauland, Michael L Dustin, Yoshinobu Koguchi, David C ParkerAbstract:Regulatory T cells (Tregs) are essential for tolerance to self and environmental Ags, acting in part by downmodulating costimulatory molecules on the surface of dendritic cells (DCs) and altering naive CD4 T cell–DC interactions. In this study, we show that Tregs form stable conjugates with DCs before, but not after, they decrease surface expression of the costimulatory molecule CD80 on the DCs. We use supported planar bilayers to show that Tregs dramatically slow down but maintain a highly polarized and motile phenotype after recognizing Ag in the absence of costimulation. These motile cells are characterized by distinct accumulations of LFA-1–ICAM-1 in the lamella and TCR-MHC in the uropod, consistent with a motile Immunological Synapse or “kinapse.” However, in the presence of high, but not low, concentrations of CD80, Tregs form stationary, symmetrical Synapses. Using blocking Abs, we show that, whereas CTLA-4 is required for CD80 downmodulation, CD28–CD80 interactions are critical for modulating Treg motility in the presence of Ag. Taken together, these results support the hypothesis that Tregs are tuned to alter their motility depending on costimulatory signals.
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polarized release of t cell receptor enriched microvesicles at the Immunological Synapse
Nature, 2014Co-Authors: Kaushik Choudhuri, Jaime Llodra, Eric W Roth, Jones Tsai, Susana Gordo, Kai W Wucherpfennig, Lance C Kam, David L Stokes, Michael L DustinAbstract:Here it is shown that T-cell receptors accumulate at the Immunological Synapse after stimulation with cognate antigen and are released in extracellular microvesicles by an ESCRT-dependent mechanism, the microvesicles deliver transcellular signals from CD4 T cells to antigen-presenting B cells and can induce B-cell signalling. T cells detect and respond to infected cells — and communicate with other immune cells — by attaching to them via specialized junctions called Immunological Synapses. How these junctions form and what communication takes place across them remain unclear. Michael Dustin and colleagues examined events at the Immunological Synapse using correlative light-electron microscopy combined with mechanistic and functional experiments. They find that the centre of the Immunological Synapse is a source of T-cell receptor (TCR)-containing extracellular microvesicles, produced by ESCRT-dependent budding. The microvesicles deliver transcellular signals from CD4+ T cells to antigen-presenting B cells, and can induce B-cell signalling. GAG protein from human immunodeficiency virus subverts this process in infected T cells as a mechanism for budding virus-like particles. The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs)1. T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the Immunological Synapse2, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft3. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the Immunological Synapse4,5, which is characterized by central accumulation of TCRs5, adjacent to a secretory domain2, both surrounded by an adhesive ring4,5. Although accumulation of TCRs at the Immunological Synapse centre correlates with T-cell function4, this domain is itself largely devoid of TCR signalling activity5,6, and is characterized by an unexplained immobilization of TCR–pMHC complexes relative to the highly dynamic Immunological Synapse periphery4,5. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the Immunological Synapse centre. Tumour susceptibility gene 101 (TSG101)6 sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4)7,8 mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the Immunological Synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent Synapses by engaging cognate pMHC on APCs.
Janis K Burkhardt - One of the best experts on this subject based on the ideXlab platform.
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the actin cytoskeleton a mechanical intermediate for signal integration at the Immunological Synapse
Frontiers in Cell and Developmental Biology, 2018Co-Authors: Nathan H Roy, Janis K BurkhardtAbstract:The Immunological Synapse (IS) is a specialized structure that serves as a platform for cell-cell communication between a T cell and an antigen-presenting cell (APC). Engagement of the T cell receptor (TCR) with cognate peptide-MHC complexes on the APC activates the T cell and instructs its differentiation. Proper T cell activation also requires engagement of additional receptor-ligand pairs, which promote sustained adhesion and deliver costimulatory signals. These events are orchestrated by T cell actin dynamics, which organize IS components and facilitate their signaling. The actin network flows from the edge of the cell inward, driving the centralization of TCR microclusters and providing the force to activate the integrin LFA-1. We recently showed that engagement of LFA-1 slows actin flow, and that this affects TCR signaling. This study highlights the physical nature of the IS, and contributes to a growing appreciation in the field that mechanosensing and mechanotransduction are essential for IS function. Additionally, it is becoming clear that there are multiple types of actin structures at the IS that promote signaling in distinct ways. How the different actin structures contribute to force production and mechanotransduction is just beginning to be explored. In this Perspective, we will feature recent work from our lab and others, that collectively points toward a model in which actin dynamics drive mechanical signaling and receptor crosstalk during T cell activation.
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integrins modulate t cell receptor signaling by constraining actin flow at the Immunological Synapse
Frontiers in Immunology, 2018Co-Authors: Katarzyna I Jankowska, Edward K Williamson, Nathan H Roy, Daniel M Blumenthal, Vidhi Chandra, Tobias Baumgart, Janis K BurkhardtAbstract:Full T cell activation requires coordination of signals from multiple receptor-ligand pairs that interact in parallel at a specialized cell-cell contact site termed the Immunological Synapse. Signaling at the Immunological Synapse is intimately associated with actin dynamics; TCR engagement induces centripetal flow of T cell actin network, which in turn enhances the function of ligand-bound integrins by promoting conformational change. Here, we have investigated the effects of integrin engagement on actin flow, and on associated signaling events downstream of the TCR. We show that integrin engagement significantly decelerates centripetal flow of the actin network. In primary CD4+ T cells, engagement of either LFA-1 or VLA-4 by their respective ligands ICAM-1 and VCAM-1 slows actin flow. Slowing of actin flow is greatest when T cells interact with low mobility integrin ligands, supporting a predominately drag-based mechanism. Using integrin ligands presented on patterned surfaces, we demonstrate that the effects of localized integrin engagement are distributed across the actin network, and that focal adhesion proteins such as talin, vinculin, and paxillin are recruited to sites of integrin engagement. Further analysis shows that talin and vinculin are interdependent upon one another for recruitment, and that ongoing actin flow is required. Suppression of vinculin or talin partially relieves integrin-dependent slowing of actin flow, indicating that these proteins serve as molecular clutches that couple engaged integrins to the dynamic actin network. Finally, we found that integrin-dependent slowing of actin flow is associated with reduction in tyrosine phosphorylation downstream of the TCR, and that this modulation of TCR signaling depends on expression of talin and vinculin. More generally, we found that integrin-dependent effects on actin retrograde flow were strongly correlated with effects on TCR signaling. Taken together, these studies support a model in which ligand-bound integrins engage the actin cytoskeletal network via talin and vinculin, and tune TCR signaling events by modulating actin dynamics at the Immunological Synapse.
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action and traction cytoskeletal control of receptor triggering at the Immunological Synapse
Frontiers in Immunology, 2016Co-Authors: William A Comrie, Janis K BurkhardtAbstract:It is well known that F-actin dynamics drive the micron-scale cell shape changes required for migration and Immunological Synapse (IS) formation. In addition, recent evidence points to a more intimate role for the actin cytoskeleton in promoting T cell activation. Mechanotransduction, the conversion of mechanical input into intracellular biochemical changes, is thought to play a critical role in several aspects of immunoreceptor triggering and downstream signal transduction. Multiple molecules associated with signaling events at the IS have been shown to respond to physical force, including the TCR, costimulatory molecules, adhesion molecules, and several downstream adapters. In at least some cases, it is clear that the relevant forces are exerted by dynamics of the T cell actomyosin cytoskeleton. Interestingly, there is evidence that the cytoskeleton of the antigen-presenting cell also plays an active role in T cell activation, by countering the molecular forces exerted by the T cell at the IS. Since actin polymerization is itself driven by TCR and costimulatory signaling pathways, a complex relationship exists between actin dynamics and receptor activation. This review will focus on recent advances in our understanding of the mechanosensitive aspects of T cell activation, paying specific attention to how F-actin-directed forces applied from both sides of the IS fit into current models of receptor triggering and activation.
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f actin flow drives affinity maturation and spatial organization of lfa 1 at the Immunological Synapse
Journal of Cell Biology, 2015Co-Authors: William A Comrie, Alexander Babich, Janis K BurkhardtAbstract:Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the Immunological Synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the Immunological Synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the Immunological Synapse.
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controversy and consensus regarding myosin ii function at the Immunological Synapse
Current Opinion in Immunology, 2013Co-Authors: John A Hammer, Janis K BurkhardtAbstract:Regulated actin dynamics play a central role in modulating signaling events at the Immunological Synapse (IS). Polymerization of actin filaments at the periphery of the IS, coupled to depolymerization near the center, generates a centripetal flow of the actin network and associated movement of signaling molecules. A recent flurry of papers addresses the role of myosin II in facilitating these events. Investigators agree that myosin II is present at the IS, where it forms actomyosin arcs within the peripheral supramolecular activation cluster, a region corresponding to the lamellum of migrating cells. However, there is substantial disagreement about the extent to which myosin II drives IS formation and signaling events leading to T cell activation.
Darrell J. Irvine - One of the best experts on this subject based on the ideXlab platform.
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t cell receptor internalization from the Immunological Synapse is mediated by tc21 and rhog gtpase dependent phagocytosis
Immunity, 2011Co-Authors: Nuria Martinezmartin, Darrell J. Irvine, Elena Fernandezarenas, Saso Cemerski, Pilar Delgado, Martin R Turner, John E Heuser, Bonnie Huang, Xose R Bustelo, Andrey S ShawAbstract:SUMMARY The Immunological Synapse (IS) serves a dual role for sustained T cell receptor (TCR) signaling and for TCR downregulation. TC21 (Rras2) is a RRas subfamily GTPase that constitutively associates with the TCR and is implicated in tonic TCR signaling by activating phosphatidylinositol 3-kinase. In this study, we demonstrate that TC21 both cotranslocates with the TCR to the IS and is necessary for TCR internalization from the IS through a mechanism dependent on RhoG, a small GTPase previously associated with phagocytosis. Indeed, we found that the TCR triggers T cells to phagocytose 1‐6 mm beads through a TC21- and RhoG-dependent pathway. We further show that TC21 and RhoG are necessary for the TCR-promoted uptake of major histocompatibility complex (MHC) from antigenpresenting cells. Therefore, TC21 and RhoG dependence underlie the existence of a common phagocytic mechanism that drives TCR internalization from the IS together with its peptide-MHC ligand.
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control of t helper cell differentiation through cytokine receptor inclusion in the Immunological Synapse
Journal of Experimental Medicine, 2009Co-Authors: Roberto A Maldonado, Darrell J. Irvine, Michelle A Soriano, Carolina L Perdomo, Kirsten Sigrist, Thomas Decker, Laurie H GlimcherAbstract:The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the Immunological Synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-γ receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-γ ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.
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synthetic surfaces as artificial antigen presenting cells in the study of t cell receptor triggering and Immunological Synapse formation
Seminars in Immunology, 2007Co-Authors: Darrell J. Irvine, Junsang DohAbstract:T cell activation occurs when T cell receptors engage peptide-major histocompatibility complex (pMHC) molecules displayed on the surface of antigen presenting cells (APCs). Clustering of TCRs and other receptors in physical patterns at the T-APC interface forms a structure known as an Immunological Synapse (IS). Studies of the IS are challenging due to the cell-cell contact context of the governing interactions. Model surfaces as synthetic APCs have thus been developed, where the type, quantity, and physical arrangement of ligands displayed to T cells are precisely controlled. These model systems have provided important insights into the structure and function of the IS.
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Immunological Synapse arrays: Patterned protein surfaces that modulate Immunological Synapse structure formation in T cells
Proceedings of the National Academy of Sciences, 2006Co-Authors: Junsang Doh, Darrell J. IrvineAbstract:T cells are activated by recognition of foreign peptides displayed on the surface of antigen presenting cells (APCs), an event that triggers assembly of a complex microscale structure at the T cell-APC interface known as the Immunological Synapse (IS). It remains unresolved whether the unique physical structure of the Synapse itself impacts the functional response of T cells, independent of the quantity and quality of ligands encountered by the T cell. As a first step toward addressing this question, we created multicomponent protein surfaces presenting lithographically defined patterns of tethered T cell receptor (TCR) ligands (anti-CD3 "activation sites") surrounded by a field of tethered intercellular adhesion molecule-1 (ICAM-1), as a model substrate on which T cells could be seeded to mimic T cell-APC interactions. CD4(+) T cells seeded on these surfaces polarized and migrated; on contact with activation sites, T cells assembled an IS with a structure modulated by the physical pattern of ligand encountered. On surfaces patterned with focal spots of TCR ligand, T cells stably interacted with activation sites, proliferated, and secreted cytokines. In contrast, T cells interacting with activation sites patterned to preclude centralized clustering of TCR ligand failed to form stable contacts with activation sites, exhibited aberrant PKC- clustering in a fraction of cells, and had significantly reduced production of IFN-gamma. These results suggest that focal clustering of TCR ligand characteristic of the "mature" IS may be required under some conditions for full T cell activation.
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t cell killing does not require the formation of a stable mature Immunological Synapse
Nature Immunology, 2004Co-Authors: Marco A Purbhoo, Darrell J. Irvine, Johannes B Huppa, Mark M. DavisAbstract:A notable feature of T lymphocyte recognition on other cell surfaces is the formation of a stable mature Immunological Synapse. Here we use a single-molecule labeling method to directly measure the number of ligands a cytotoxic T cell engages and track the consequences of that interaction by three-dimensional video microscopy. Like helper T cells, cytotoxic T cells were able to detect even a single foreign antigen but required about ten complexes of peptide-major histocompatibility complex (pMHC) to achieve full calcium increase and to form a mature Synapse. Thus, cytotoxic T cells and helper T cells are more uniform in their antigen sensitivities than previously thought. Furthermore, only three pMHC complexes were required for killing, showing that stable Synapse formation and complete signaling are not required for cytotoxicity.
Jordan S Orange - One of the best experts on this subject based on the ideXlab platform.
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Formation and function of the lytic NK-cell Immunological Synapse
Nature Reviews Immunology, 2008Co-Authors: Jordan S OrangeAbstract:The natural killer (NK)-cell Immunological Synapse is the dynamic interface formed between an NK cell and its target cell. Formation of the NK-cell Immunological Synapse involves several distinct stages, from the initiation of contact with a target cell to the directed delivery of lytic-granule contents for target-cell lysis. Progression through the individual stages is regulated, and this tight regulation underlies the precision with which NK cells select and kill susceptible target cells (including virally infected cells and cancerous cells) that they encounter during their routine surveillance of the body.
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cdc42 interacting protein 4 functionally links actin and microtubule networks at the cytolytic nk cell Immunological Synapse
Journal of Experimental Medicine, 2007Co-Authors: Pinaki P Banerjee, Jordan S Orange, Rahul Pandey, Rena Zheng, Megan M Suhoski, Linda MonacoshawverAbstract:An essential function of the Immunological Synapse (IS) is directed secretion. NK cells are especially adept at this activity, as they direct lytic granules to the Synapse for secretion, which enables cytotoxicity and facilitates host defense. This initially requires rearrangement of the actin cytoskeleton and, subsequently, microtubule-dependent trafficking of the lytic granules. As these two steps are sequential, specific linkages between them are likely to serve as critical regulators of cytotoxicity. We studied Cdc42-interacting protein–4 (CIP4), which constitutively interacts with tubulin and microtubules but focuses to the microtubule organizing center (MTOC) after NK cell activation, when it is able to associate with Wiskott-Aldrich syndrome protein (WASp) and the actin filament–rich IS. WASp deficiency, overexpression of CIP4, or parts of CIP4 interfere with this union and block normal CIP4 localization, MTOC polarization to the IS, and cytotoxicity. Reduction of endogenous CIP4 expression using small interfering RNA similarly inhibits MTOC polarization and cytotoxic activity but does not impair actin filament accumulation at the IS, or Cdc42 activation. Thus, CIP4 is an important cytoskeletal adaptor that functions after filamentous actin accumulation and Cdc42 activation to enable MTOC polarization and NK cell cytotoxicity.
Chen Liu - One of the best experts on this subject based on the ideXlab platform.
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the role of Immunological Synapse in predicting the efficacy of chimeric antigen receptor car immunotherapy
Cell Communication and Signaling, 2020Co-Authors: Dongfang Liu, Gianpietro Dotti, Saiaditya Badeti, Jiegen Jiang, He Wang, James Dermody, Patricia Soteropoulos, Deanna Streck, Raymond B Birge, Chen LiuAbstract:Chimeric Antigen Receptor (CAR) immunotherapy utilizes genetically-engineered immune cells that express a unique cell surface receptor that combines tumor antigen specificity with immune cell activation. In recent clinical trials, the adoptive transfer of CAR-modified immune cells (including CAR-T and CAR-NK cells) into patients has been remarkably successful in treating multiple refractory blood cancers. To improve safety and efficacy, and expand potential applicability to other cancer types, CARs with different target specificities and sequence modifications are being developed and tested by many laboratories. Despite the overall progress in CAR immunotherapy, conventional tools to design and evaluate the efficacy and safety of CAR immunotherapies can be inaccurate, time-consuming, costly, and labor-intensive. Furthermore, existing tools cannot always determine how responsive individual patients will be to a particular CAR immunotherapy. Recent work in our laboratory suggests that the quality of the Immunological Synapse (IS) can accurately predict CAR-modified cell efficacy (and toxicity) that can correlate with clinical outcomes. Here we review current efforts to develop a Synapse Predicts Efficacy (SPE) system for easy, rapid and cost-effective evaluation of CAR-modified immune cell immunotherapy. Ultimately, we hypothesize the conceptual basis and clinical application of SPE will serve as an important parameter in evaluating CAR immunotherapy and significantly advance precision cancer immunotherapy. Video abstract Graphic abstract for manuscript CCAS-D-20-00136 by Liu, D., et al., 'The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy". The various branches of evaluating cancer immunotherapy metaphorically represented as a Rubik's cube. The development of a novel approach to predict the effectiveness of Chimeric Antigen Receptor (CAR)-modified cells by quantifying the quality of CAR IS will introduce a new parameter to the rapidly expanding field of cancer immunotherapy. Currently, no single parameter can predict the clinical outcome or efficacy of a specific type of CAR-modified cell. IS quality will serve as a quantifiable measure to evaluate CAR products and can be used in conjunction with other conventional parameters to form a composite clinical predictor. Much like a Rubik's cube has countless configurations, several methods and combinations of clinical metrics have arisen for evaluating the ability of a given immunotherapeutic strategy to treat cancer. The quality of IS depicting cancer immunotherapy is metaphorically expressed as a Rubik's cube. Each face/color represents one aspect of cancer therapy. Each grid in one face indicates one factor within that aspect of cancer therapy. For example, the green color represents the tumor microenvironment, and one out of the nine grids in the green color indicates suppressor cells (suppressors in green). Changes in one factor may completely alter the entire strategy of cancer therapy. However, the quality of IS (illuminated center red grid) makes the effectiveness of CAR immunotherapy predictable.
