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TCR signaling

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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
#1
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/29765373/compartmentalized-cyclic-amp-production-by-the-bordetella-pertussis-and-bacillus-anthracis-adenylate-cyclase-toxins-differentially-affects-the-immune-synapse-in-t-lymphocytes
#2
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
#3
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
#4
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/29754419/integration-of-t-cell-receptor-notch-and-cytokine-signals-programs-in-mouse-%C3%AE-%C3%AE-t-cell-effector-differentiation
#5
Payam Zarin, Tracy S H In, Edward L Y Chen, Jastaranpreet Singh, Gladys W Wong, Mahmood Mohtashami, David L Wiest, Michele K Anderson, Juan Carlos Zúñiga-Pflücker
γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2-/- T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines...
May 13, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29752423/strong-homeostatic-tcr-signals-induce-formation-of-self-tolerant-virtual-memory-cd8-t-cells
#6
Ales Drobek, Alena Moudra, Daniel Mueller, Martina Huranova, Veronika Horkova, Michaela Pribikova, Robert Ivanek, Susanne Oberle, Dietmar Zehn, Kathy D McCoy, Peter Draber, Ondrej Stepanek
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells...
May 11, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29752063/proteomic-analyses-of-human-regulatory-t-cells-reveal-adaptations-in-signaling-pathways-that-protect-cellular-identity
#7
Eloy Cuadrado, Maartje van den Biggelaar, Sander de Kivit, Yi-Yen Chen, Manon Slot, Ihsane Doubal, Alexander Meijer, Rene A W van Lier, Jannie Borst, Derk Amsen
To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways...
May 5, 2018: Immunity
https://www.readbyqxmd.com/read/29747685/car-t-cell-therapy-for-breast-cancer-harnessing-the-tumor-milieu-to-drive-t-cell-activation
#8
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/29740438/the-nkg2d-nkg2dl-axis-in-the-crosstalk-between-lymphoid-and-myeloid-cells-in-health-and-disease
#9
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/29740052/viper-regulates-naive-t-cell-activation-and-effector-responses-implication-in-tlr4-associated-acute-stage-t-cell-responses
#10
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/29736031/nuclear-pore-complex-mediated-modulation-of-tcr-signaling-is-required-for-na%C3%A3-ve-cd4-t-cell-homeostasis
#11
Joana Borlido, Stephen Sakuma, Marcela Raices, Florent Carrette, Roberto Tinoco, Linda M Bradley, Maximiliano A D'Angelo
Nuclear pore complexes (NPCs) are channels connecting the nucleus with the cytoplasm. We report that loss of the tissue-specific NPC component Nup210 causes a severe deficit of naïve CD4+ T cells. Nup210-deficient CD4+ T lymphocytes develop normally but fail to survive in the periphery. The decreased survival results from both an impaired ability to transmit tonic T cell receptor (TCR) signals and increased levels of Fas, which sensitize Nup210-/- naïve CD4+ T cells to Fas-mediated cell death. Mechanistically, Nup210 regulates these processes by modulating the expression of Cav2 (encoding Caveolin-2) and Jun at the nuclear periphery...
May 7, 2018: Nature Immunology
https://www.readbyqxmd.com/read/29734372/the-adaptor-molecule-cd2ap-in-cd4-t-cells-modulates-differentiation-of-follicular-helper-t-cells-during-chronic-lcmv-infection
#12
Saravanan Raju, Kohei Kometani, Tomohiro Kurosaki, Andrey S Shaw, Takeshi Egawa
CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine is incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection...
May 7, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29729204/outcome-of-anti-viral-immunity-in-the-liver-is-shaped-by-the-level-of-antigen-expressed-in-infected-hepatocytes
#13
Katrin Manske, Nina Kallin, Verena König, Annika Schneider, Sandra Kurz, Miriam Bosch, Meike Welz, Ru-Lin Cheng, Bertram Bengsch, Katja Steiger, Ulrike Protzer, Robert Thimme, Percy A Knolle, Dirk Wohlleber
The liver bears unique immune-properties supporting both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remains unclear. Here, we dissect the factors determining the outcome of anti-viral immunity using novel recombinant adenoviruses reflecting the hepatropism and -trophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar ovalbumin, luciferase and GFP-expression driven by strong ubiquitous CMV-promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific Transthyretin(TTR)-promoter (Ad-TTR-GOL)...
May 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29722021/differential-tcr-signals-for-t-helper-cell-programming
#14
REVIEW
Penelope A Morel
Upon encounter with their cognate antigen naïve CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen presenting cells, cytokines and costimulatory molecules. The strength of the T cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength...
May 2, 2018: Immunology
https://www.readbyqxmd.com/read/29720981/the-neutral-sphingomyelinase-2-is-required-to-polarize-and-sustain-t-cell-receptor-signaling
#15
Charlene Börtlein, Annette Draeger, Roman Schoenauer, Alexander Kuhlemann, Markus Sauer, Sibylle Schneider-Schaulies, Elita Avota
By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca2+ mobilization and T cell proliferation...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29719024/molecular-advances-in-cutaneous-t-cell-lymphoma
#16
Armando N Bastidas Torres, Safa Najidh, Cornelis P Tensen, Maarten H Vermeer
Cutaneous T-cell lymphoma (CTCL) is a group of malignancies derived from skin-homing T cells. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common CTCL variants. In recent years, the genetic landscape of SS/MF has been characterized using genome-wide nextgeneration sequencing approaches. These studies have revealed that genes subjected to oncogenic mutations take part in cell cycle regulation, chromatin modification, Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) signaling, T-cell receptor (TCR)/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and microtubule associated protein kinase (MAPK) signaling, which suggests that deregulation of these cellular processes underlies lymphomagenesis...
March 2018: Seminars in Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/29717064/glycerol-monolaurate-induces-filopodia-formation-by-disrupting-the-association-between-lat-and-slp-76-microclusters
#17
Michael S Zhang, Phuong M Tran, Alexander J Wolff, Mikaela M Tremblay, Micaela G Fosdick, Jon C D Houtman
Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)-induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen-presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures but instead developed numerous inappropriate actin-mediated filopodia...
May 1, 2018: Science Signaling
https://www.readbyqxmd.com/read/29713322/tcr-signaling-abnormalities-in-human-th2-associated-atopic-disease
#18
REVIEW
Joshua D Milner
Stimulation of naïve CD4 T cells with weak T cell receptor agonists even in the absence of T helper-skewing cytokines can result in IL-4 production which can drive a Th2 response. Evidence for the in vivo consequences of such a phenomenon can be found in a number of mouse models and, importantly, a series of monogenic human diseases associated with significant atopy which are caused by mutations in the T cell receptor signaling cascade. Such diseases can help understand how Th2 responses evolve in humans, and potentially provide insight into therapeutic interventions...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29705245/role-of-human-foxp3-in-early-thymic-maturation-and-peripheral-t-cell-homeostasis
#19
F R Santoni de Sio, L Passerini, S Restelli, M M Valente, A Pramov, M E Maccari, F Sanvito, M G Roncarolo, M Porteus, R Bacchetta
BACKGROUND: FOXP3 is a key transcription factor in regulatory T cell (Treg) function. FOXP3 gene mutations cause IPEX, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T cells (Teff) but to date this role has not been confirmed. OBJECTIVE: To evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with the IPEX immune pathology. METHODS: We developed a humanized mouse model in which the human hematopoietic system is stably knocked down (KD) or knocked out (KO) for the FOXP3 gene (KD/KO huMice)...
April 26, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29704254/intrahepatic-t-cell-receptor-%C3%AE-immune-repertoire-is-essential-for-liver-regeneration
#20
Qing Liang, Zeyuan Liu, Chao Zhu, Bin Wang, Xiaoke Liu, Yanan Yang, Xue Lv, Haiyu Mu, Kejia Wang
T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High-throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRβ immune repertoire in liver regeneration. We investigated the hepatic regeneration in TCRβ chain-deficient (Tcrb-/- ) mice by two-thirds partial hepatectomy (PHx) method...
April 27, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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