Formation and Function of the Lytic NK‑Cell Immunological Synapse

Total Page:16

File Type:pdf, Size:1020Kb

Formation and Function of the Lytic NK‑Cell Immunological Synapse REVIEWS Formation and function of the lytic NK-cell immunological synapse Jordan S. Orange Abstract | 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. ‘Danger’ signals Natural killer (NK) cells are lymphocytes of the innate of lytic-granule contents in NK cells compared with the Agents that alert the immune immune system that elicit effector functions following process in CTLs. Indeed, direct comparisons between system to danger and thereby the ligation of germline-encoded receptors. In humans, the cytolytic process in NK cells and CTLs have identified promote the generation of NK cells are able to deliver a response immediately after important kinetic and mechanistic differences2. immune responses. Danger recognizing specific signals, including stress signals, The induction of many NK-cell effector functions, signals can be associated with microbial invaders (exogenous ‘danger’ signals or signals from molecules of foreign including cytotoxicity, requires that the NK cell contacts danger signals), and can also origin. They were originally described as having rapid its target cell. This ensures precise targeting of the cytolytic be produced or expressed by cell-mediated cytotoxicity. However, they are now also process to a single diseased cell in a tissue without affect- damaged cells (endogenous known to promote slower receptor-mediated apopto- ing its neighbouring cells. The events that occur following danger signals). sis, to provide contact-dependent co-stimulation and the interaction between a cytolytic cell and its target cell to efficiently produce soluble mediators, including have been well studied. They include the delivery and cytokines. NK cells therefore participate in the defence secretion of cytolytic effector molecules at the interface against infections, the regulation of immune responses that is formed between the cytotoxic cell and its target cell and the surveillance of stressed or cancerous cells through a process known as directed secretion. (reviewed in REF. 1). Although these functions are not Our understanding of directed secretion for cyto- unique to NK cells, they use NK-cell-specific receptor toxicity has been advanced by the discovery of the systems, and the ability to mediate effector functions immunological synapse. The immunological synapse rapidly without the need to develop further is a key was originally defined in the late 1990s3,4 as the crucial distinguishing feature between mature NK cells and junction between a T cell and an antigen-presenting cell cytotoxic T lymphocytes (CTLs), both of which are (APC) at which T-cell receptors (TCRs) interact with efficient at mediating cytotoxicity. MHC molecules. Subsequent studies extended these NK-cell cytotoxicity involves the secretion of cyto- observations and identified relevant immunological lytic effector molecules from specialized organelles that synapses between different types of immune cell, as University of Pennsylvania are known as lytic granules. Much of what is known well as between immune cells and non-immune cells. School of Medicine, Joseph about this process is derived from studies of CTLs and Thus, an immunological synapse can be defined as the Stokes Jr Research Institute this has provided guidance for subsequent studies of NK orderly rearrangement of molecules in an immune cell of The Children’s Hospital of Philadelphia, 3615 Civic cells. However, there are several important differences at the interface with another cell. Numerous molecules Center Boulevard, ARC between NK cells and CTLs, and so the processes lead- have been identified as participating in the immunologi- 1016H, Philadelphia, ing to cytotoxicity by the two cell types should not be cal synapse, including receptors, signalling molecules, Pennsylvania 19104, USA. assumed to be identical. For example, the lytic granules cytoskeletal elements and cellular organelles. Some stud- e-mail: [email protected]. are preformed in resting human NK cells but not in ies suggest that these molecules accumulate in distinct upenn.edu doi:10.1038/nri2381 CTLs. As a result, the cytolytic process in NK cells needs regions in an activating immunological synapse to form Published online to be well regulated, and this might involve additional a supramolecular activation cluster (SMAC), which may 18 August 2008 or enhanced mechanisms for controlling the secretion be segregated into peripheral (pSMAC) and central NATURE REVIEWS | IMMUNOLOGY VOLUME 8 | SEPTEMBER 2008 | 713 REVIEWS Microclusters (cSMAC) zones. However, the purpose of this molecular Lytic granules are hybrid organelles that are special- Discrete collections patterning is debatable, as functions typically attributed ized for the secretion of the lytic effector molecules of molecules at the to the SMAC can be induced in its absence under some which reside in them (BOX 2). For an NK cell to mediate immunological synapse that circumstances5. Furthermore, single molecule studies cytotoxicity, lytic granules are emptied onto a target can move in the plasma (FIG. 1) membrane and generate and kinetic studies of the immunological synapse have cell at a prototypical mature lytic synapse . In signals. They are smaller than shown that, in some settings, the engagement of indi- the mature synapse, filamentous actin (F-actin) and and exclusive of the central vidual receptors6 or the involvement of microclusters of adhesion receptors accumulate and are thought to supramolecular activation cell-surface and signalling molecules can support cell form a ring in the pSMAC through which perforin and cluster, which can represent activation without the need for a mature synapse7,8. other lytic-granule contents are secreted. Domains in a coalescence of multiple microclusters. Therefore, the importance of larger scale accumulations the lytic synapse that contain specific signalling mol- and distinct segregation of molecules at the synapse is ecules or secretory machinery have been described Perforin currently being re-evaluated. in CTLs9, but may not always be required for CTL- A component of cytolytic 6 Although debate regarding the role of the immuno- mediated cytotoxicity . Similar molecule distribution granules that participates in the permeabilization of plasma logical synapse in enabling immune responses con- patterns have been observed in NK cells, albeit incon- 10–12 membranes, thereby allowing tinues, several of its potential functions seem relevant sistently , and many aspects of NK-cell synapse granzymes and other cytotoxic and worth considering (BOX 1). Many of these functions organization have not been elucidated. However, lytic components to enter or be were originally assigned to the immunological synapse granules are large organelles and must traverse dense taken up by target cells. between a T helper cell and an APC, but they also apply F-actin networks at the synapse, and actin reorganiza- to the NK-cell synapse. Certain aspects, however, are tion is required for their release. Therefore, synapse more relevant to NK cells, such as the directed secretion formation has the specific function in NK cells of of lytic granules for cytotoxicity. enabling cytotoxicity. Box 1 | Proposed functions of the immunological synapse There are numerous functions ascribed to the immunological synapse, many of which are relevant to natural killer (NK) cells. Ligand recognition. The immunological synapse creates a crucial zone where ligands can be recognized accurately by their cognate receptors among many non-relevant ligands. Signal amplification and integration. Whether in large clusters at the central supramolecular activation cluster (cSMAC) or in discrete microclusters that are located in the periphery, important signalling molecules localize with receptors at the synapse. Innovative studies in NK cells have described functional signalling at these sites40, as well as functional integration of signals11. Co-stimulation. Co-stimulatory ligands, such as CD40 ligand116 and OX40L ligand117, that are expressed by NK cells can bind receptors on adaptive immune cells to facilitate immune responses. In vivo, NK cells have been shown to engage with other innate cells and T cells simultaneously118. The innate cell presumably induces the expression of NK-cell co-stimulatory ligands, which are then recognized by adjoining T cells. Cytotoxicity. The close approximation of an NK cell and its target cell that is conferred by the immunological synapse ensures precise targeting of cytotoxicity31 and can protect neighbouring cells from the damaging effects of cytotoxic mediators. Directed secretion. The arrangement of molecules at the synapse can create a conduit through which cellular components can be secreted9. Linkage between the synapse and intracellular transport machinery allows the focused secretion of small and large components, including lytic granules21 and cytokines119. Multidirectional secretion. Activation signals originating from molecules in the synapse can induce secretion at sites away
Recommended publications
  • Sialic Acids and Their Influence on Human NK Cell Function
    cells Review Sialic Acids and Their Influence on Human NK Cell Function Philip Rosenstock * and Thomas Kaufmann Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Hollystr. 1, D-06114 Halle/Saale, Germany; [email protected] * Correspondence: [email protected] Abstract: Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function. Keywords: sialic acids; sialylation; NK cells; Siglecs; NCAM; CD56; sialyltransferases; NKp44; Nkp46; NKG2D 1. Introduction 1.1. Sialic Acids N-Acetylneuraminic acid (Neu5Ac) is the most common sialic acid in the human organism and also the precursor for all other sialic acid derivatives. The biosynthesis of Neu5Ac begins in the cytosol with uridine diphosphate-N-acetylglucosamine (UDP- Citation: Rosenstock, P.; Kaufmann, GlcNAc) as its starting component [1]. It is important to understand that sialic acid T. Sialic Acids and Their Influence on formation is strongly linked to glycolysis, since it results in the production of fructose-6- Human NK Cell Function. Cells 2021, phosphate (F6P) and phosphoenolpyruvate (PEP).
    [Show full text]
  • Coordination of T Cell Activation and Migration Through Formation of the Immunological Synapse
    Coordination of T Cell Activation and Migration through Formation of the Immunological Synapse MICHAEL L. DUSTIN Program in Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine and the Department of Pathology, New York University School of Medicine, New York, New York 10016, USA ABSTRACT: T cell activation is based on interactions of T cell antigen receptors with MHC-peptide complexes in a specialized cell–cell junction between the T cell and antigen-presenting cell—the immunological synapse. The immunolog- ical synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen-presenting cells bearing appropriate major histo- compatibility complex (MHC) peptide complexes. At the same time, the immu- nological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activa- tion through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell re- ceptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self- stabilized structure that is correlated with cytokine production and prolifera- tion. I propose that this molecular pattern and its specific biochemical constit- uents are necessary
    [Show full text]
  • The Immunological Synapse and CD28-CD80 Interactions Shannon K
    © 2001 Nature Publishing Group http://immunol.nature.com ARTICLES The immunological synapse and CD28-CD80 interactions Shannon K. Bromley1,Andrea Iaboni2, Simon J. Davis2,Adrian Whitty3, Jonathan M. Green4, Andrey S. Shaw1,ArthurWeiss5 and Michael L. Dustin5,6 Published online: 19 November 2001, DOI: 10.1038/ni737 According to the two-signal model of T cell activation, costimulatory molecules augment T cell receptor (TCR) signaling, whereas adhesion molecules enhance TCR–MHC-peptide recognition.The structure and binding properties of CD28 imply that it may perform both functions, blurring the distinction between adhesion and costimulatory molecules. Our results show that CD28 on naïve T cells does not support adhesion and has little or no capacity for directly enhancing TCR–MHC- peptide interactions. Instead of being dependent on costimulatory signaling, we propose that a key function of the immunological synapse is to generate a cellular microenvironment that favors the interactions of potent secondary signaling molecules, such as CD28. The T cell receptor (TCR) interaction with complexes of peptide and as CD2 and CD48, which suggests that CD28 might have a dual role as major histocompatibility complex (pMHC) is central to the T cell an adhesion and a signaling molecule4. Coengagement of CD28 with response. However, efficient T cell activation also requires the partici- the TCR has a number of effects on T cell activation; these include pation of additional cell-surface receptors that engage nonpolymorphic increasing sensitivity to TCR stimulation and increasing the survival of ligands on antigen-presenting cells (APCs). Some of these molecules T cells after stimulation5. CD80-transfected APCs have been used to are involved in the “physical embrace” between T cells and APCs and assess the temporal relationship of TCR and CD28 signaling, as initiat- are characterized as adhesion molecules.
    [Show full text]
  • Dissociation the Immunological Synapse Upon Cellular T Cells
    Peptide-Specific Intercellular Transfer of MHC Class II to CD4 + T Cells Directly from the Immunological Synapse upon Cellular Dissociation This information is current as of September 26, 2021. Scott A. Wetzel, Timothy W. McKeithan and David C. Parker J Immunol 2005; 174:80-89; ; doi: 10.4049/jimmunol.174.1.80 http://www.jimmunol.org/content/174/1/80 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2004/12/16/174.1.80.DC1 Material http://www.jimmunol.org/ References This article cites 53 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/174/1/80.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Peptide-Specific Intercellular Transfer of MHC Class II to CD4؉ T Cells Directly from the Immunological Synapse upon Cellular Dissociation1 Scott A.
    [Show full text]
  • 553.Full.Pdf
    Cutting Edge: DNAX Accessory Molecule 1− Deficient CD8+ T Cells Display Immunological Synapse Defects That Impair Antitumor Immunity This information is current as of October 4, 2021. Kelly M. Ramsbottom, Edwin D. Hawkins, Raz Shimoni, Mairi McGrath, Christopher J. Chan, Sarah M. Russell, Mark J. Smyth and Jane Oliaro J Immunol 2014; 192:553-557; Prepublished online 13 December 2013; Downloaded from doi: 10.4049/jimmunol.1302197 http://www.jimmunol.org/content/192/2/553 Supplementary http://www.jimmunol.org/content/suppl/2013/12/13/jimmunol.130219 http://www.jimmunol.org/ Material 7.DC1 References This article cites 25 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/192/2/553.full#ref-list-1 Why The JI? Submit online. by guest on October 4, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Cutting Edge Immunology Cutting Edge: DNAX Accessory Molecule 1–Deficient CD8+ T Cells Display Immunological Synapse Defects That Impair Antitumor Immunity Kelly M.
    [Show full text]
  • Immunological Synapse CD28 Signals in the Immature
    CD28 Signals in the Immature Immunological Synapse Pietro G. Andres, Kimberly C. Howland, Douglas Dresnek, Samuel Edmondson, Abul K. Abbas and Matthew F. This information is current as Krummel of September 28, 2021. J Immunol 2004; 172:5880-5886; ; doi: 10.4049/jimmunol.172.10.5880 http://www.jimmunol.org/content/172/10/5880 Downloaded from References This article cites 25 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/172/10/5880.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD28 Signals in the Immature Immunological Synapse1 Pietro G. Andres,2†‡ Kimberly C. Howland,2* Douglas Dresnek,†‡ Samuel Edmondson,†‡ Abul K. Abbas,* and Matthew F. Krummel3* T cell recognition of peptide-MHC complexes on APCs results in the aggregation of TCRs at a central supramolecular activation complex (c-SMAC) within a mature immunological synapse.
    [Show full text]
  • Studies of the Role of Sialyl Lewis X Antigen and E Selectin Ligands in Colorectal Cancer
    Fanny Marjolaine Deschepper Mestre em Biologia-Saude Studies of the role of sialyl Lewis X antigen and E selectin ligands in colorectal cancer Dissertação para obtenção do Grau de Doutor em Biologia - Especialidade em Biologia Celular Orientador: Doutora Paula Alexandra Quintela Videira, Profa. Auxiliar, Faculdade de Ciências e Tecnologia - Universidade Nova de Lisboa Co-orientador: Doutor Fabio Dall'Olio, Professor, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale - Università di Bologna Júri: Presidente: Profa. Doutora Isabel Maria Godinho de Sá Nogueira Arguentes: Profa. Doutora Susana Constantino Rosa Santos Invª. Doutora Salomé Soares de Pinho Vogais: Invª. Doutora Maria Angelina de Sá Palma Profa. Doutora Paula Alexandra Quintela Videira Fevereiro 2020 Fanny Marjolaine Deschepper Studies of the role of sialyl Lewis X antigen and E-selectin ligands in colorectal cancer Copyright © Fanny Deschepper, FCT/UNL, UNL A Faculdade de Ciências e Tecnologia e a Universidade Nova de Lisboa têm o direito, perpétuo e sem limites geográficos, de arquivar e publicar esta dissertação através de exemplares impressos reproduzidos em papel ou de forma digital, ou por qualquer outro meio conhecido ou que venha a ser inventado, e de a divulgar através de repositórios científicos e de admitir a sua cópia e distribuição com objetivos educacionais ou de investigação, não comerciais, desde que seja dado crédito ao autor e editor. iii Acknowledgements To begin, I would like to thank my supervisor Dr Paula Videira for giving me the opportunity to be part of this great project. I am grateful for the confidence and support she gave to me during this PhD project. A special thanks goes to my co-supervisor Fabio Dall’Olio, and to my collaborators, Dr Paul Hensbergen and Dr Daniel Spencer, who welcomed me in their respective laboratories and gave me the opportunity to enlarge my knowledges and scientific skills by teaching me new techniques and analysis approaches.
    [Show full text]
  • The Immunological Synapse and the Actin Cytoskeleton: Molecular Hardware for T Cell Signaling Michael L
    © 2000 Nature America Inc. • http://immunol.nature.com REVIEW The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling Michael L. Dustin1 and John A. Cooper2 The actin cytoskeleton seems to play two critical CD58—to bring cells to within 15 nm of each other, by formation of roles in the activation of T cells.One of these roles thousands of transient, low affinity interactions23,27–30. T cells are sensi- tive to small numbers of MHC-peptide complexes on the APC31. Precise is T cell shape development and movement, includ- alignment of apposing membranes at ∼15 nm is probably essential for ing formation of the immunological synapse. The this high sensitivity. However, small adhesion molecules such as CD2 other is the formation of a scaffold for signaling and CD58 are also prevented by the glycocalyx from interacting and 32 components. This review focuses on the recent require active processes to initiate adhesion . The integrin LFA-1 and its major immunoglobulin superfamily ligand ICAM-1 can interact at .com convergence of cell biology and immunology stud- ∼40 nm and can thereby initiate adhesive interactions when appropri- e ies to explain the role of the actin cytoskeleton in ately activated33,34. These large adhesion molecules initiate active mech- creating the molecular basis for immunological anisms to promote the interaction of smaller adhesion molecules, bring- synapse formation and T cell signaling. ing the actin cytoskeleton to center stage. The actin cytoskeleton plays a dual role in regulation of LFA-1. The resting leukocyte has two surface domains: low flat surfaces and Two roles of the actin cytoskeleton in T cell activation microvilli.
    [Show full text]
  • CD80 and CD86 Differentially Regulate Mechanical Interactions of T-Cells with Antigen-Presenting Dendritic Cells and B-Cells
    CD80 and CD86 Differentially Regulate Mechanical Interactions of T-Cells with Antigen-Presenting Dendritic Cells and B-Cells Tong Seng Lim1*, James Kang Hao Goh1, Alessandra Mortellaro1, Chwee Teck Lim2,3, Gu¨ nter J. Ha¨mmerling4, Paola Ricciardi-Castagnoli1* 1 Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore, 2 Mechanobiology Institute, National University of Singapore, Singapore, Singapore, 3 Department of Bioengineering & Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore, 4 Division of Molecular Immunology, German Cancer Research Center DKFZ, Heidelberg, Germany Abstract Functional T-cell responses are initiated by physical interactions between T-cells and antigen-presenting cells (APCs), including dendritic cells (DCs) and B-cells. T-cells are activated more effectively by DCs than by B-cells, but little is known about the key molecular mechanisms that underpin the particular potency of DC in triggering T-cell responses. To better understand the influence of physical intercellular interactions on APC efficacy in activating T-cells, we used single cell force spectroscopy to characterize and compare the mechanical forces of interactions between DC:T-cells and B:T-cells. Following antigen stimulation, intercellular interactions of DC:T-cell conjugates were stronger than B:T-cell interactions. DCs induced higher levels of T-cell calcium mobilization and production of IL-2 and IFNc than were elicited by B-cells, thus suggesting that tight intercellular contacts are important in providing mechanically stable environment to initiate T-cell activation. Blocking antibodies targeting surface co-stimulatory molecules CD80 or CD86 weakened intercellular interactions and dampen T-cell activation, highlighting the amplificatory roles of CD80/86 in regulating APC:T-cell interactions and T-cell functional activation.
    [Show full text]
  • Formation of a Central Supramolecular Activation Cluster Is Not Required for Activation of Naive CD8؉ T Cells
    Formation of a central supramolecular activation cluster is not required for activation of naive CD8؉ T cells James P. O’Keefe*†, Kelly Blaine‡, Maria-Luisa Alegre‡§, and Thomas F. Gajewski*†‡§¶ Committees on *Cancer Biology and §Immunology and Departments of †Pathology and ‡Medicine, University of Chicago, Chicago, IL 60637 Edited by Arthur Weiss, University of California School of Medicine, San Francisco, CA, and approved May 5, 2004 (received for review September 16, 2003) Although both naive and effector T lymphocytes interact with facilitates directional release of cytokines and other effector antigen-expressing cells, the functional outcome of these interac- molecules toward antigen-expressing targets (6, 7). This model tions is distinct. Naive CD8؉ T cells are activated to proliferate and might predict distinct properties of the immune synapse between differentiate into effector cytolytic T lymphocytes (CTL), whereas naive T cells, which lack effector function, and primed effector CTL interact with specific targets, such as tumor cells, to induce T cells, which produce effector cytokines and can possess apoptotic death. We recently observed that several molecules cytolytic activity. linked to actin cytoskeleton dynamics were up-regulated in effec- Using Affymetrix (Santa Clara, CA) gene arrays, we recently tor vs. naive CD8؉ T cells, leading us to investigate whether T cell observed that several molecules linked to actin cytoskeletal differentiation is accompanied by changes in actin-dependent dynamics were up-regulated in effector T cells compared with ,processes. We observed that both naive and effector CD8؉ T cells naive CD8ϩ TCR transgenic T cells (8). This observation underwent T cell receptor capping and formed stable conjugates coupled with the fact that most analyses of the immunologic with antigen-specific antigen-presenting cells.
    [Show full text]
  • Αβ T Cell Receptor Mechanosensing Forces out Serial Engagement
    Opinion αb T Cell Receptor Mechanosensing Forces out Serial Engagement Yinnian Feng,1 Ellis L. Reinherz,2,3,* and Matthew J. Lang1,4,* T lymphocytes use αb T cell receptors (TCRs) to recognize sparse antigenic Highlights peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting The αb TCR is a mechanosensor cells (APCs). Contrary to conventional receptor–ligand associations exempli- whose force-dependent structural transition and allostery regulate pep- fied by antigen–antibody interactions, forces play a crucial role in nonequilib- tide discrimination and pMHC bond rium mechanosensor-based T cell activation. Both T cell motility and local lifetime. cytoskeleton machinery exert forces (i.e., generate loads) on TCR–pMHC Application of mechanical force on the bonds. We review biological features of the load-dependent activation process TCR during ligand recognition pro- as revealed by optical tweezers single molecule/single cell and other biophysi- motes its molecular translocation and fi initiates T cell immunological synapse cal measurements. The ndings link pMHC-triggered TCRs to single cytoskel- formation. etal motors; define the importance of energized anisotropic (i.e., force direction dependent) activation; and characterize immunological synapse formation as Synergy of external (cell motility based) and internal (cytoskeletal motor based) digital, revealing no serial requirement. The emerging picture suggests new forces supports a nonequilibrium approaches for the monitoring and design of cytotoxic T lymphocyte (CTL)- (energized) model for T cell activation fi α based immunotherapy. through recon guration of the b TCR complex at a critical force threshold. αb Biophysical Mechanism of TCR Triggering via an Energized Process A digital mechanosensing mechanism αb T cells specifically recognize foreign peptides displayed on infected or otherwise perturbed defines physicochemical thresholds cells through a process that discriminates with exquisite specificity.
    [Show full text]
  • Immunological Synapse of CTL and CD3
    Lipid Rafts Mediate Association of LFA-1 and CD3 and Formation of the Immunological Synapse of CTL This information is current as Muhammad Reza Marwali, Matthew A. MacLeod, David N. of September 23, 2021. Muzia and Fumio Takei J Immunol 2004; 173:2960-2967; ; doi: 10.4049/jimmunol.173.5.2960 http://www.jimmunol.org/content/173/5/2960 Downloaded from References This article cites 37 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/173/5/2960.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Lipid Rafts Mediate Association of LFA-1 and CD3 and Formation of the Immunological Synapse of CTL1 Muhammad Reza Marwali,* Matthew A. MacLeod,* David N. Muzia,* and Fumio Takei2*† Lipid rafts accumulate in the immunological synapse formed by an organized assembly of the TCR/CD3, LFA-1, and signaling molecules.
    [Show full text]