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Immunological synapse

Greger Abrahamsen, Vibeke Sundvold-Gjerstad, Meseret Habtamu, Bjarne Bogen, Anne Spurkland
Polarization of T cells towards the antigen presenting cell (APC) is critically important for appropriate activation and differentiation of the naïve T cell. Here we used imaging flow cytometry (IFC) and show that the activation induced Lck and Itk adapter T cell specific adapter protein (TSAd), encoded by SH2D2A, modulates polarization of T cells towards the APC. Upon exposure to APC presenting the cognate antigen Id, Sh2d2a-/- CD4+ T cells expressing Id-specific transgenic T cell receptor (TCR), displayed impaired polarization of F-actin and TCR to the immunological synapse (IS)...
September 6, 2018: Scientific Reports
Michal Stawarski, Karlis Anthony Justs, Roberto Xander Hernandez, Gregory Talisker Macleod
Membrane proteins play a lead role in the formation and function of synapses, but, despite revolutions in immunology and molecular genetics, limitations persist in our ability to investigate membrane proteins in the context of an intact synapse. Here, we introduce a simple but novel approach to resolving the distribution of endogenous membrane proteins in either live or fixed tissues. The technique involves transgenic expression of a protein with an extracellular tag, a generic transmembrane domain, and an intracellular terminus that mimics the intracellular anchoring motifs of the endogenous protein of interest...
September 3, 2018: Journal of Neurogenetics
Ilenia Papa, Carola G Vinuesa
The germinal center (GC) is a complex, highly dynamic microanatomical niche that allows the generation of high-affinity antibody-producing plasma cells and memory B cells. These cells constitute the basis of long-lived highly protective antibody responses. For affinity maturation to occur, B cells undergo multiple rounds of proliferation and mutation of the genes that encode the immunoglobulin V region followed by selection by specialized T cells called follicular helper T (TFH ) cells. In order to achieve this result, the GC requires spatially and temporally coordinated interactions between the different cell types, including B and T lymphocytes and follicular dendritic cells...
2018: Frontiers in Immunology
Rebecca J Bayliss, Vincent Piguet
In order to thrive, viruses have evolved to manipulate host cell machinery for their own benefit. One major obstacle faced by pathogens is the immunological synapse. To enable efficient replication and latency in immune cells viruses have developed a range of strategies to manipulate cellular processes involved in IS formation to evade immune detection and control T-cell activation. In vitro, viruses such as HIV-1 and HTLV-1 utilise structures known as virological synapses to aid transmission of viral particles from cell-to-cell in a process termed trans-infection...
August 19, 2018: Cellular Microbiology
Antoun Al Absi, Hannah Wurzer, Coralie L Guerin, Céline Hoffmann, Flora Moreau, Xianqing Mao, Joshua Brown-Clay, Rémi Petrolli, Carla Pou Casellas, Monika Dieterle, Jean Paul Thiery, Salem Chouaib, Guy Berchem, Bassam Janji, Clement Thomas
Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic NK cells. A significant fraction of breast cancer cells responded to NK cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunological synapse, a process we termed 'actin response'. Live cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK cell-mediated cell death...
August 13, 2018: Cancer Research
Anastasios Siokis, Philippe A Robert, Philippos Demetriou, Michael L Dustin, Michael Meyer-Hermann
During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS)...
July 31, 2018: Cell Reports
Daniel Schlam, Sergio Grinstein, Spencer A Freeman
Rho GTPases, a family of molecular switches, are essential for the assembly and rearrangement of the cellular actin network. Actin remodeling is a central component of many important biological phenomena including chemotaxis, immunological synapse formation, and phagocytosis. Proper execution of these processes requires careful modulation of Rho GTPase activity in space and time. This is accomplished by delicate coordination of Rho GTPase activation and inactivation by Rho guanine nucleotide exchange factors (RhoGEFs) and Rho GTPase-activating proteins (RhoGAPs), respectively...
2018: Methods in Molecular Biology
Sonja M Lacher, Christoph Thurm, Ute Distler, Alma N Mohebiany, Nicole Israel, Maja Kitic, Anna Ebering, Yilang Tang, Matthias Klein, Guido H Wabnitz, Florian Wanke, Yvonne Samstag, Tobias Bopp, Florian C Kurschus, Luca Simeoni, Stefan Tenzer, Ari Waisman
NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT ) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics...
July 27, 2018: Journal of Autoimmunity
Yinnian Feng, Ellis L Reinherz, Matthew J Lang
T lymphocytes use αβ T cell receptors (TCRs) to recognize sparse antigenic peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting cells (APCs). Contrary to conventional receptor-ligand associations exemplified by antigen-antibody interactions, forces play a crucial role in nonequilibrium mechanosensor-based T cell activation. Both T cell motility and local cytoskeleton machinery exert forces (i.e., generate loads) on TCR-pMHC bonds. We review biological features of the load-dependent activation process as revealed by optical tweezers single molecule/single cell and other biophysical measurements...
August 2018: Trends in Immunology
Caroline Junqueira, Camila R R Barbosa, Pedro A C Costa, Andréa Teixeira-Carvalho, Guilherme Castro, Sumit Sen Santara, Rafael P Barbosa, Farokh Dotiwala, Dhelio B Pereira, Lis R Antonelli, Judy Lieberman, Ricardo T Gazzinelli
Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2 . The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4 . Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6 . Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite...
September 2018: Nature Medicine
Samuel W French, Jiajie G Lu
The nature of the immunologic synapse in autoimmune hepatitis is defined. This process involves the T cell receptor (TCR) which binds to the hepatocyte antigen presenting major histocompatibility complex (MHC) on the plasma membrane. This complex is quickly removed from the liver cell and taken into the T cell cytoplasm to be digested by the lysosome. The liver cell is gradually diminished to the point of its total removal by the lymphocytes binding to it.
August 2018: Experimental and Molecular Pathology
Yu Tai, Qingtong Wang, Heinrich Korner, Lingling Zhang, Wei Wei
The interaction between T cell and dendritic cells (DCs) that leads to T cell activation affects the progression of the immune response including autoimmune diseases. Antigen presentation on immune cell surface, formation of an immunological synapse (IS), and specific identification of complex by T cells including two activating signals are necessary steps that lead to T cell activation. The formation of stimulatory IS involves the inclusion of costimulatory molecules, such as ICAM-1/LFA-1 and CD28/B7-1, and so on...
2018: Frontiers in Pharmacology
Matthieu Sawaf, Jean-Daniel Fauny, Renaud Felten, Flora Sagez, Jacques-Eric Gottenberg, Hélène Dumortier, Fanny Monneaux
Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls...
July 12, 2018: JCI Insight
Ruby Peters, Juliette Griffié, Garth L Burn, David J Williamson, Dylan M Owen
Single molecule localization microscopy (SMLM) methods produce data in the form of a spatial point pattern (SPP) of all localized emitters. Whilst numerous tools exist to quantify molecular clustering in SPP data, the analysis of fibrous structures has remained understudied. Taking the SMLM localization coordinates as input, we present an algorithm capable of tracing fibrous structures in data generated by SMLM. Based upon a density parameter tracing routine, the algorithm outputs several fibre descriptors, such as number of fibres, length of fibres, area of enclosed regions and locations and angles of fibre branch points...
July 10, 2018: Scientific Reports
Grzegorz Chodaczek, Monika Toporkiewicz, M Anna Zal, Tomasz Zal
Dendritic epidermal T cells (DETCs) represent a prototypical lineage of intraepithelial γδ T cells that participate in the maintenance of body barrier homeostasis. Unlike classical T cells, DETCs do not recirculate and they remain persistently activated through their T cell receptors (TCR) at steady state, i.e., in absence of infection or tissue wounding. The steady state TCR signals sustain the formation of immunological synapse-like phosphotyrosine-rich aggregates located on projections (PALPs) which act to anchor and polarize DETC's long cellular projections toward the apical epidermis while the cell bodies reside in the basal layers...
2018: Frontiers in Immunology
Ryan H Newton, Sharad Shrestha, Jenna M Sullivan, Kathleen B Yates, Ewoud B Compeer, Noga Ron-Harel, Bruce R Blazar, Steven J Bensinger, W Nicholas Haining, Michael L Dustin, Daniel J Campbell, Hongbo Chi, Laurence A Turka
Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions...
July 9, 2018: Nature Immunology
N Martin-Blanco, R Blanco, C Alda-Catalinas, E R Bovolenta, C L Oeste, E Palmer, W W Schamel, G Lythe, C Molina-París, M Castro, B Alarcon
The T-cell antigen receptor (TCR) is pre-organised in oligomers, known as nanoclusters. Nanoclusters could provide a framework for inter-TCR cooperativity upon peptide antigen-major histocompatibility complex (pMHC) binding. Here we have used soluble pMHC oligomers in search for cooperativity effects along the plasma membrane plane. We find that initial binding events favour subsequent pMHC binding to additional TCRs, during a narrow temporal window. This behaviour can be explained by a 3-state model of TCR transition from Resting to Active, to a final Inhibited state...
July 5, 2018: Nature Communications
Frank Stenner, Christoph Renner
Follicular lymphoma (FL) is the most frequent indolent lymphoma in the Western world and is characterized in almost all cases by the t(14;18) translocation that results in overexpression of BCL2, an anti-apoptotic protein. The entity includes a spectrum of subentities that differ from an indolent to a very aggressive growth pattern. As a consequence, treatment can include watch & wait up to intensive chemotherapy including allogeneic stem cell transplantation. The immune cell microenvironment has been recognized as a major driver of outcome of FL patients and gene expression profiling has identified a clinically relevant gene expression signature that classifies an immune response to the lymphoma cells...
2018: Frontiers in Oncology
Vishal Khairnar, Vikas Duhan, Ashwini M Patil, Fan Zhou, Hilal Bhat, Christine Thoens, Piyush Sharma, Tom Adomati, Sarah-Kim Friendrich, Judith Bezgovsek, Janine D Dreesen, Gunther Wennemuth, Astrid M Westendorf, Gennadiy Zelinskyy, Ulf Dittmer, Cornelia Hardt, Jörg Timm, Joachim R Göthert, Philipp A Lang, Bernhard B Singer, Karl S Lang
Dysfunction of CD8+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse...
July 2, 2018: Nature Communications
M Xipell, I Victoria, V Hoffmann, J Villarreal, A García-Herrera, O Reig, L Rodas, M Blasco, E Poch, B Mellado, L F Quintana
Direct stimulation of the antitumor activity of immune system through checkpoint inhibitors (ICIs) has demonstrated efficacy in the treatment of different cancer types. The activity of these antibodies takes place in the immunological synapse blocking the binding of the negative immunoregulatory proteins, thus leading to the finalization of the immune response. Despite having a favorable toxicity profile, its mechanism of action impedes the negative regulation of the immune activity which can potentially favor autoimmune attacks to normal tissues...
2018: Oncoimmunology
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