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Immunological synapse

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.
July 12, 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
Finetti Francesca, Cosima T Baldari
The development of T cell mediated immunity relies on the assembly of a highly specialized interface between T cell and antigen presenting cell (APC), known as the immunological synapse (IS). IS assembly is triggered when the T cell receptor (TCR) binds to specific peptide antigen presented in association to the major histocompatibility complex (MHC) by the APC, and is followed by the spatiotemporal dynamic redistribution of TCR, integrins, co-stimulatory receptors and signaling molecules, allowing for the fine-tuning and integration of the signals that lead to T cell activation...
June 10, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Aravindhan Ganesan, Theinmozhi Arulraj, Tahir Choulli, Khaled H Barakat
BACKGROUND: Monoclonal antibodies blocking the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor have revolutionized the field of anti-cancer therapy for the last few years. The human T-cell-based immune responses are modulated by two contradicting signals. CTLA-4 provides a T cell inhibitory signal through its interaction with B7 ligands (B7-1 and B7-2), while CD28 provides a stimulatory signal when interacting with the same ligands. A previous theoretical model has focused on understanding the processes of costimulatory and inhibitory complex formations at the synapse...
June 11, 2018: BMC Medical Informatics and Decision Making
Amr H Allam, Mirren Charnley, Sarah M Russell
Cell polarity is an essential process shared by almost all animal tissues. Moreover, cell polarity enables cells to sense and respond to the cues provided by the neighboring cells and the surrounding microenvironment. These responses play a critical role in regulating key physiological processes, including cell migration, proliferation, differentiation, vesicle trafficking and immune responses. The polarity protein complexes regulating these interactions are highly evolutionarily conserved between vertebrates and invertebrates...
June 8, 2018: Journal of Molecular Biology
Moran Galperin, Carine Farenc, Madhura Mukhopadhyay, Dhilshan Jayasinghe, Amandine Decroos, Daniela Benati, Li Lynn Tan, Lisa Ciacchi, Hugh H Reid, Jamie Rossjohn, Lisa A Chakrabarti, Stephanie Gras
Rare individuals, termed HIV controllers, spontaneously control HIV infection by mounting efficient T cell responses against the virus. Protective CD4+ T cell responses from HIV controllers involve high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope...
June 8, 2018: Science Immunology
Richard Kasprowicz, Emma Rand, Peter J O'Toole, Nathalie Signoret
Cell-to-cell communication engages signaling and spatiotemporal reorganization events driven by highly context-dependent and dynamic intercellular interactions, which are difficult to capture within heterogeneous primary cell cultures. Here, we present a straightforward correlative imaging approach utilizing commonly available instrumentation to sample large numbers of cell-cell interaction events, allowing qualitative and quantitative characterization of rare functioning cell-conjugates based on calcium signals...
May 22, 2018: Scientific Reports
Elisa Sanchez, Morgan Huse
T lymphocytes engage in rapid, polarized signaling, occurring within minutes following TCR activation. This induces formation of the immunological synapse, a stereotyped cell-cell junction that regulates T cell activation and directionally targets effector responses. To study these processes effectively, an imaging approach that is tailored to capturing fast, polarized responses is necessary. This protocol describes such a system, which is based on a photoactivatable peptide-major histocompatibility complex (pMHC) that is non-stimulatory until it is exposed to ultraviolet light...
April 25, 2018: Journal of Visualized Experiments: JoVE
Laurène Pfajfer, Nina K Mair, Raúl Jiménez-Heredia, Ferah Genel, Nesrin Gulez, Ömür Ardeniz, Birgit Hoeger, Sevgi Köstel Bal, Christoph Madritsch, Artem Kalinichenko, Rico Chandra Ardy, Bengü Gerçeker, Javier Rey-Barroso, Hanna Ijspeert, Stuart G Tangye, Ingrid Simonitsch-Klupp, Johannes B Huppa, Mirjam van der Burg, Loïc Dupré, Kaan Boztug
BACKGROUND: The actin-interacting protein WD repeat-containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. OBJECTIVE: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. METHODS: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes...
May 8, 2018: Journal of Allergy and Clinical Immunology
Suin Jo, Hye-Ran Kim, YeVin Mun, Chang-Duk Jun
Transgelin-2 is a small 22-kDa actin-binding protein implicated in actin dynamics, which stabilizes actin structures and participates in actin-associated signaling pathways. Much curiosity regarding transgelin-2 has centered around its dysregulation in tumor development and associated diseases. However, recent studies have shed new light on the functions of transgelin-2, the only transgelin family member present in leukocytes, in the context of various immune responses. In this review, we outlined the biochemical properties of transgelin-2 and its physiological functions in T cells, B cells, and macrophages...
May 11, 2018: Journal of Leukocyte Biology
Björn Bulitta, Werner Zuschratter, Isabel Bernal, Dunja Bruder, Frank Klawonn, Martin von Bergen, Henrikus Stephanus Paulus Garritsen, Lothar Jänsch
Mucosal-associated invariant T cells (MAIT) constitute the most abundant anti-bacterial CD8+ T-cell population in humans. MR1/TCR-activated MAIT cells were reported to organize cytotoxic and innate-like responses but knowledge about their molecular effector phenotype is still fragmentary. Here, we have examined the functional inventory of human MAIT cells (CD3+ Vα7.2+ CD161+ ) in comparison with those from conventional non-MAIT CD8+ T cells (cCD8+ ) and NK cells. Quantitative mass spectrometry characterized 5500 proteins of primary MAIT cells and identified 160 and 135 proteins that discriminate them from cCD8+ T cells and NK cells donor-independently...
May 11, 2018: European Journal of Immunology
Jie Geng, John D Altman, Sujatha Krishnakumar, Malini Raghavan
When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode...
May 9, 2018: ELife
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