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https://www.readbyqxmd.com/read/29789604/plasma-membrane-lat-activation-precedes-vesicular-recruitment-defining-two-phases-of-early-t-cell-activation
#1
Lakshmi Balagopalan, Jason Yi, Tiffany Nguyen, Katherine M McIntire, Adam S Harned, Kedar Narayan, Lawrence E Samelson
The relative importance of plasma membrane-localized LAT versus vesicular LAT for microcluster formation and T-cell receptor (TCR) activation is unclear. Here, we show the sequence of events in LAT microcluster formation and vesicle delivery, using lattice light sheet microscopy to image a T cell from the earliest point of activation. A kinetic lag occurs between LAT microcluster formation and vesicular pool recruitment to the synapse. Correlative 3D light and electron microscopy show an absence of vesicles at microclusters at early times, but an abundance of vesicles as activation proceeds...
May 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29789296/tuning-itam-multiplicity-on-t-cell-receptors-can-control-potency-and-selectivity-to-ligand-density
#2
John R James
The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted into an intracellular signal...
May 22, 2018: Science Signaling
https://www.readbyqxmd.com/read/29784674/clinically-relevant-cytotoxic-immune-cell-signatures-and-clonal-expansion-of-t-cell-receptors-in-high-risk-mycn-not-amplified-human-neuroblastoma
#3
Jun S Wei, Igor B Kuznetsov, Shile Zhang, Young K Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Sushma Nagaraj, Ashley Walton, Jaime M Guidry Auvil, Daniela S Gerhard, Aysen Yuksel, Daniel R Catchpoole, Stephen M Hewitt, Paul M Sondel, Robert C Seeger, John M Maris, Javed Khan
PURPOSE: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). EXPERIMENTAL DESIGN: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas...
May 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29783736/revisiting-cd28-superagonist-tgn1412-as-potential-therapeutic-for-pediatric-b-cell-leukemia-a-review
#4
REVIEW
Katelyn E Brown
Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (TReg ) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell...
May 19, 2018: Diseases (Basel)
https://www.readbyqxmd.com/read/29777027/t-cell-proliferation-and-colitis-are-initiated-by-defined-intestinal-microbes
#5
Pailin Chiaranunt, Justin T Tometich, Junyi Ji, Timothy W Hand
Inflammatory bowel disease has been associated with the dysregulation of T cells specific to Ags derived from the intestinal microbiota. How microbiota-specific T cells are regulated is not completely clear but is believed to be mediated by a combination of IgA, regulatory T cells, and type 3 innate lymphoid cells. To test the role of these regulatory components on microbiota-specific T cells, we bred CBir1 TCR transgenic (CBir1Tg) mice (specific to flagellin from common intestinal bacteria) onto a lymphopenic Rag1-/- background...
May 18, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29776088/how-nonuniform-contact-profiles-of-t-cell-receptors-modulate-thymic-selection-outcomes
#6
Hanrong Chen, Arup K Chakraborty, Mehran Kardar
T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies...
March 2018: Physical Review. E
https://www.readbyqxmd.com/read/29770136/cd3%C3%AE%C2%B5-expression-defines-functionally-distinct-subsets-of-v%C3%AE-1-t-cells-in-patients-with-human-immunodeficiency-virus-infection
#7
Pádraic J Dunne, Christina O Maher, Michael Freeley, Katie Dunne, Andreea Petrasca, Judy Orikiiriza, Margaret R Dunne, Derval Reidy, Siobhan O'Dea, Aisling Loy, Jim Woo, Aideen Long, Thomas R Rogers, Fiona Mulcahy, Derek G Doherty
Human γδ T cells expressing the Vδ1 T cell receptor (TCR) recognize self and microbial antigens and stress-inducible molecules in a major histocompatibility complex-unrestricted manner and are an important source of innate interleukin (IL)-17. Vδ1 T cells are expanded in the circulation and intestines of patients with human immunodeficiency virus (HIV) infection. In this study, we show that patients with HIV have elevated frequencies, but not absolute numbers, of circulating Vδ1 T cells compared to control subjects...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29765548/transformation-of-mouse-t-cells-requires-myc-and-akt-activity-in-conjunction-with-inhibition-of-intrinsic-apoptosis
#8
Kari Högstrand, Stephanie Darmanin, TachaZi Plym Forshell, Alf Grandien
Peripheral T-cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by excessive proliferation of transformed mature T cells. The number and nature of genetic aberrations required and sufficient for transformation of normal T cells into lymphomas is unknown. Here, using a combinatorial in vitro -approach, we demonstrate that overexpression of MYC together with activated AKT in conditions of inhibition of intrinsic apoptosis rapidly resulted in transformation of mature mouse T cells with a frequency approaching 100%...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29765373/compartmentalized-cyclic-amp-production-by-the-bordetella-pertussis-and-bacillus-anthracis-adenylate-cyclase-toxins-differentially-affects-the-immune-synapse-in-t-lymphocytes
#9
Vijay B Arumugham, Cristina Ulivieri, Anna Onnis, Francesca Finetti, Fiorella Tonello, Daniel Ladant, Cosima T Baldari
A central feature of the immune synapse (IS) is the tight compartmentalization of membrane receptors and signaling mediators that is functional for its ability to coordinate T cell activation. Second messengers centrally implicated in this process, such as Ca2+ and diacyl glycerol, also undergo compartmentalization at the IS. Current evidence suggests a more complex scenario for cyclic AMP (cAMP), which acts both as positive and as negative regulator of T-cell antigen receptor (TCR) signaling and which, as such, must be subjected to a tight spatiotemporal control to allow for signaling at the IS...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29757266/spatial-and-temporal-control-of-t-cell-activation-using-a-photoactivatable-agonist
#10
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
https://www.readbyqxmd.com/read/29755980/importance-of-validating-antibodies-and-small-compound-inhibitors-using-genetic-knockout-studies-t-cell-receptor-induced-cyld-phosphorylation-by-ikk%C3%AE%C2%B5-tbk1-as-a-case-study
#11
Marie Lork, Marja Kreike, Jens Staal, Rudi Beyaert
CYLD is a deubiquitinating enzyme that plays a crucial role in immunity and inflammation as a negative regulator of NF-κB transcription factor and JNK kinase signaling. Defects in either of these pathways contribute to the progression of numerous inflammatory and autoimmune disorders. Therefore, we set out to unravel molecular mechanisms that control CYLD activity in the context of T cell receptor (TCR) signaling. More specifically, we focused on CYLD phosphorylation at Ser418, which can be detected upon immunoblotting of cell extracts with phospho(Ser418)-CYLD specific antibodies...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29751004/mutations-affecting-the-actin-regulator-wdr1-lead-to-aberrant-lymphoid-immunity
#12
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 WDR1 promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have recently been identified in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. OBJECTIVE: Given the pleiotropic expression of WDR1, we here investigated to what extent it might control the lymphoid arm of the immune system in humans. METHODS: Histological and detailed immunological analyses were performed to elucidate the role of WDR1 in development and function of B and T lymphocytes...
May 8, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29749611/proteomic-definition-of-human-mucosal-associated-invariant-t-cells-determines-their-unique-molecular-effector-phenotype
#13
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
https://www.readbyqxmd.com/read/29747685/car-t-cell-therapy-for-breast-cancer-harnessing-the-tumor-milieu-to-drive-t-cell-activation
#14
Pradip Bajgain, Supannikar Tawinwung, Lindsey D'Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K Brenner, Ann M Leen, Juan F Vera
BACKGROUND: The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site...
May 10, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29741477/empty-conformers-of-hla-b-preferentially-bind-cd8-and-regulate-cd8-t-cell-function
#15
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
https://www.readbyqxmd.com/read/29740438/the-nkg2d-nkg2dl-axis-in-the-crosstalk-between-lymphoid-and-myeloid-cells-in-health-and-disease
#16
REVIEW
Ana Stojanovic, Margareta P Correia, Adelheid Cerwenka
Natural killer group 2, member D (NKG2D) receptor is a type II transmembrane protein expressed by both innate and adaptive immune cells, including natural killer (NK) cells, CD8+ T cells, invariant NKT cells, γδ T cells, and some CD4+ T cells under certain pathological conditions. NKG2D is an activating NK receptor that induces cytotoxicity and production of cytokines by effector cells and supports their proliferation and survival upon engagement with its ligands. In both innate and T cell populations, NKG2D can costimulate responses induced by other receptors, such as TCR in T cells or NKp46 in NK cells...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29740432/unique-and-common-features-of-innate-like-human-v%C3%AE-2-%C3%AE-%C3%AE-t-cells-and-mucosal-associated-invariant-t-cells
#17
Nicholas M Provine, Benedikt Binder, Michael E B FitzPatrick, Anita Schuch, Lucy C Garner, Kate D Williamson, Bonnie van Wilgenburg, Robert Thimme, Paul Klenerman, Maike Hofmann
Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29740052/viper-regulates-naive-t-cell-activation-and-effector-responses-implication-in-tlr4-associated-acute-stage-t-cell-responses
#18
Subhransu Sekhar Sahoo, Belluru M Pratheek, Vikram S Meena, Tapas Kumar Nayak, P Sanjai Kumar, Saumya Bandyopadhyay, Prasanta Kumar Maiti, Subhasis Chattopadhyay
Naive T cells are known to express the modest level of TLR4 while it is known to go down during TCR activation. However, information towards the requirement of TLR4 signaling during TCR or mitogenic activation of naive wild-type T cells remains scanty. Here we have investigated the endogenous functional expression of TLR4 in naive mice T cells during TCR and mitogenic stimulation in presence of VIPER peptide (VP), an established inhibitor of TLR4 signaling. As expected we found that TLR4 expression goes down during TCR and mitogenic activation...
May 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29735518/-brucella-peptide-cross-reactive-mhc-i-presentation-activates-siinfekl-specific-tcr-expressing-t-cells
#19
Jerome S Harms, Mike Khan, Cherisse Hall, Gary A Splitter, E Jane Homan, Robert D Bremel, Judith A Smith
Brucella spp are intracellular pathogenic bacteria remarkable in their ability to escape immune surveillance and therefore inflict a state of chronic disease within the host. To enable further immune response studies, Brucella were engineered to express the well characterized chicken ovalbumin (OVA). Surprisingly, we found that CD8 T cells bearing T cell receptors (TCR) nominally specific for the OVA peptide SIINFEKL (OT-1) reacted to parental Brucella -infected targets as well as OVA-expressing Brucella variants in cytotoxicity assays...
May 7, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29730909/-establishment-of-the-culture-system-of-%C3%AE-%C3%AE-t-cells-in-vitro-and-the-anti-tumor-effect
#20
L Xie, W Chen, L Wang, M Cheng, S L Hu, G Shen
Objective: To establish the culture technique for culturing γδ T cells in vitro and evaluate the basic characteristics, security and anti-tumor effect of the cultured γδ T cells. Methods: Phytohemagglutinin, zoledronic acid, interleukin-2 and interleukin -7 were used to induce the abundant expansion of peripheral blood mononuclear cells in vitro . Flow cytometry assay, in vitro killing assay and mouse model of human lung cancer were also adopted to assess the characteristics and the anti-tumor effect of cultured γδ T cells...
April 23, 2018: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
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