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TCR signalling

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https://www.readbyqxmd.com/read/29146547/a-gene-module-associated-with-dysregulated-tcr-signaling-pathways-in-cd4-t-cell-subsets-in-rheumatoid-arthritis
#1
Shuji Sumitomo, Yasuo Nagafuchi, Yumi Tsuchida, Haruka Tsuchiya, Mineto Ota, Kazuyoshi Ishigaki, Shinichiro Nakachi, Rika Kato, Keiichi Sakurai, Norio Hanata, Shoko Tateishi, Hiroko Kanda, Akari Suzuki, Yuta Kochi, Keishi Fujio, Kazuhiko Yamamoto
We analyzed the transcriptome of detailed CD4(+) T cell subsets including them after abatacept treatment, and examined the difference among CD4(+) T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4(+) T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500...
November 13, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29143824/pd-1-is-a-haploinsufficient-suppressor-of-t-cell-lymphomagenesis
#2
Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad, Jürgen Ruland
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events...
November 15, 2017: Nature
https://www.readbyqxmd.com/read/29142309/hypercholesterolemia-enhances-t-cell-receptor-signaling-and-increases-the-regulatory-t-cell-population
#3
Reiner K W Mailer, Anton Gisterå, Konstantinos A Polyzos, Daniel F J Ketelhuth, Göran K Hansson
Hypercholesterolemia promotes the inflammation against lipoproteins in atherosclerosis. Development of atherosclerosis is affected by the balance between pro-inflammatory effector T cells and anti-inflammatory regulatory T (Treg) cells. However, phenotype and function of T cell subpopulations in hypercholesterolemia remain to be investigated. Here, we found that cholesterol-containing diet increased the expression of the Treg cell lineage-defining transcription factor FoxP3 among thymocytes and splenocytes...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29142275/nf-%C3%AE%C2%BAb-protects-nkt-cells-from-tumor-necrosis-factor-receptor-1-induced-death
#4
Amrendra Kumar, Laura E Gordy, Jelena S Bezbradica, Aleksandar K Stanic, Timothy M Hill, Mark R Boothby, Luc Van Kaer, Sebastian Joyce
Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-xL-coding Bcl2l1 transgene into NF-κB signalling-deficient IκBΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29129580/the-%C3%AE-and-%C3%AE-2%C3%AE-auxiliary-subunits-of-cav1-channels-are-required-for-th2-lymphocyte-function-and-acute-allergic-airway-inflammation
#5
Nicolas Rosa, Emily Triffaux, Virginie Robert, Marion Mars, Martin Klein, Gregory Bouchaud, Astrid Canivet, Antoine Magnan, Jean-Charles Guéry, Lucette Pelletier, Magali Savignac
BACKGROUND: T-lymphocytes express not only the cell membrane calcium ORAI1 but also voltage-dependent Cav1 channels. In excitable cells, these channels are composed of the ion forming pore α1 and auxiliary subunits (β and α2δ) needed for proper trafficking and activation of the channel. We previously disclosed the role of Cav1.2 α1 in mouse and human Th2- but not Th1-cell functions and showed that knocking-down Cav1 α1 prevents experimental asthma OBJECTIVE: We investigated the role of β and α2δ auxiliary subunits on Cav1 α1 function in Th2 lymphocytes and on the development of acute allergic airway inflammation...
November 9, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29127148/ubc9-binds-to-adap-and-is-required-for-rap1-membrane-recruitment-rac1-activation-and-integrin-mediated-t-cell-adhesion
#6
Yiwei Xiong, Chengjin Ye, Naiqi Yang, Madanqi Li, Hebin Liu
Although the immune adaptor adhesion and degranulation-promoting adaptor protein (ADAP) acts as a key mediator of integrin inside-out signaling leading to T cell adhesion, the regulation of this adaptor during integrin activation and clustering remains unclear. We now identify Ubc9, the sole small ubiquitin-related modifier E2 conjugase, as an essential regulator of ADAP where it is required for TCR-induced membrane recruitment of the small GTPase Rap1 and its effector protein RapL and for activation of the small GTPase Rac1 in T cell adhesion...
November 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29125738/profiling-of-protein-o-glcnacylation-in-murine-cd8-effector-and-memory-like-t-cells
#7
Aime Lopez Aguilar, Yu Gao, Xiaomeng Hou, Gregoire Lauvau, John R Yates, Peng Wu
During an acute infection, antigenic stimulation leads to activation, expansion, and differentiation of naïve CD8(+) T cells, first into cytotoxic effector cells and eventually into long-lived memory cells. T cell antigen receptors (TCRs) detect antigens on antigen-presenting cells (APCs) in the form of antigenic peptides bound to major histocompatibility complex I (MHC-I)-encoded molecules and initiate TCR signal transduction network. This process is mediated by phosphorylation of many intracellular signaling proteins...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29117183/capacity-of-ttreg-generation-is-not-impaired-in-the-atrophied-thymus
#8
Jiyoung Oh, Weikan Wang, Rachel Thomas, Dong-Ming Su
Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models...
November 8, 2017: PLoS Biology
https://www.readbyqxmd.com/read/29111199/density-dependent-re-tuning-of-autoreactive-t-cells-alleviates-their-pathogenicity-in-a-lymphopenic-environment
#9
Eleanore Chuang, Marilyn Augustine, Matthew Jung, Ronald H Schwartz, Nevil J Singh
Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells...
December 2017: Immunology Letters
https://www.readbyqxmd.com/read/29109121/glycogen-synthase-kinase-3-modulates-cbl-b-and-constrains-t-cell-activation
#10
Charles W Tran, Samuel D Saibil, Thierry Le Bihan, Sara R Hamilton, Karl S Lang, Han You, Amy E Lin, Kristine M Garza, Alisha R Elford, Kelly Tai, Michael E Parsons, Kip Wigmore, Mitchell G Vainberg, Josef M Penninger, James R Woodgett, Tak W Mak, Pamela S Ohashi
The decision between T cell activation and tolerance is governed by the spatial and temporal integration of diverse molecular signals and events occurring downstream of TCR and costimulatory or coinhibitory receptor engagement. The PI3K-protein kinase B (PKB; also known as Akt) signaling pathway is a central axis in mediating proximal signaling events of TCR and CD28 engagement in T cells. Perturbation of the PI3K-PKB pathway, or the loss of negative regulators of T cell activation, such as the E3 ubiquitin ligase Cbl-b, have been reported to lead to increased susceptibility to autoimmunity...
November 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29106696/the-mechanisms-shaping-the-repertoire-of-cd4-foxp3-treg-cells
#11
REVIEW
Piotr Kraj, Leszek Ignatowicz
Regulatory T (Treg ) cells expressing Foxp3 transcription factor control homeostasis of the immune system, antigenic responses to commensal and pathogenic microbiota, and immune responses to self and tumor antigens. Treg cells differentiate in the thymus, (tTreg ) along with conventional CD4(+) T cells, in processes of positive and negative selection. Another class of Treg cells is generated in peripheral tissues (pTreg ) by inducing Foxp3 expression in conventional CD4(+) T cells in response to antigenic stimulation...
November 6, 2017: Immunology
https://www.readbyqxmd.com/read/29105157/reduced-numbers-of-mature-medullary-thymic-epithelial-cells-in-skg-mice
#12
Robby Engelmann, Andra Biemelt, Anja Johl, Daniela Kuthning, Brigitte Müller-Hilke
Attenuated T cell receptor (TCR) signaling contributes to the susceptibility for autoimmunity as shown via mutants of PTPN22 and Zap70 genes. We here set out to investigate the effect of an attenuated TCR signal on the composition of the thymic epithelial cell (TEC) compartment. To that extent, we combined flow cytometry and histology and compared the TEC subpopulations of Zap70 wild type with SKG mutant mice. We found an increased cortical TEC compartment in SKG thymi at the expense of reduced numbers of mature medullary TECs and a 4...
November 3, 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29101227/nmr-directed-design-of-pretcr%C3%AE-and-pmhc-molecules-implies-a-distinct-geometry-for-pretcr-relative-to-%C3%AE-%C3%AE-tcr-recognition-of-pmhc
#13
Robert J Mallis, Haribabu Arthanari, Matthew John Lang, Ellis L Reinherz, Gerhard Wagner
The pre-T cell receptor (preTCR) guides early thymocytes through maturation processes within the thymus via interaction with self ligands displayed on thymic epithelial cells. The preTCR is a disulfide-linked heterodimer composed of an invariant preTα (pTα) subunit and a variable β subunit, the latter of which is incorporated into the mature T cell receptor (TCR) in subsequent developmental progression. This interaction of preTCR with peptide-major histocompatibility complex molecules (pMHC) has recently been shown to drive robust preTCR signaling and thymocyte maturation...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29101209/oral-epithelial-cells-orchestrate-innate-type-17-responses-to-candida-albicans-through-the-virulence-factor-candidalysin
#14
Akash H Verma, Jonathan P Richardson, Chunsheng Zhou, Bianca M Coleman, David L Moyes, Jemima Ho, Anna R Huppler, Kritika Ramani, Mandy J McGeachy, Ilgiz A Mufazalov, Ari Waisman, Lawrence P Kane, Partha S Biswas, Bernhard Hube, Julian R Naglik, Sarah L Gaffen
Candida albicans is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of C. albicans hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to C. albicans During the innate response, IL-17 is produced by γδ T cells and a poorly understood population of innate-acting CD4(+) αβ T cell receptor (TCRαβ)(+) cells, but only the TCRαβ(+) cells expand during acute infection...
November 3, 2017: Science Immunology
https://www.readbyqxmd.com/read/29093082/according-to-hcv-infection-stage-il-7-plus-4-1bb-triggering-alone-or-combined-with-pd-1-blockade-increases-traf1-low-hcv-specific-cd8-cell-reactivity
#15
Elia Moreno-Cubero, Dolores Subirá, Eduardo Sanz-de-Villalobos, Trinidad Parra-Cid, Antonio Madejón, Joaquín Miquel, Antonio Olveira, Alejandro González-Praetorius, Javier García-Samaniego, Juan-Ramón Larrubia
Hepatitis C virus (HCV)-specific CD8(+) T cells suffer a progressive exhaustion during persistent HCV infection (PI). This process could involve the positive immune checkpoint 4-1BB/4-1BBL, through the loss of its signal transducer TRAF1. To address this issue, peripheral HCV-specific CD8(+) T cells (Pentamer(+)/CD8(+)) from patients with PI and resolved infection after treatment (RI) were studied. Duration of HCV infection and liver fibrosis progression rate inversely correlated with the likelihood of detecting peripheral pentamer(+)/CD8(+) cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29083415/encoding-optical-control-in-lck-kinase-to-quantitatively-investigate-its-activity-in-live-cells
#16
Ardiyanto Liaunardy-Jopeace, Ben L Murton, Mohan Mahesh, Jason W Chin, John R James
LCK is a tyrosine kinase that is essential for initiating T-cell antigen receptor (TCR) signaling. A complete understanding of LCK function is constrained by a paucity of methods to quantitatively study its function within live cells. To address this limitation, we generated LCK*, in which a key active-site lysine is replaced by a photocaged equivalent, using genetic code expansion. This strategy enabled fine temporal and spatial control over kinase activity, thus allowing us to quantify phosphorylation kinetics in situ using biochemical and imaging approaches...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29079582/c-mpl-provides-tumor-targeted-t-cell-receptor-transgenic-t-cells-with-co-stimulation-and-cytokine-signals
#17
Christopher D Nishimura, Daniel A Brenner, Malini Mukherjee, Rachel A Hirsch, Leah Ott, Meng-Fen Wu, Hao Liu, Olga Dakhova, Jordan S Orange, Malcolm K Brenner, Charles Y Lin, Caroline Arber
Adoptively transferred T cell receptor (TCR)-engineered T-cells depend on host-derived co-stimulation and cytokine signals for their full and sustained activation. However, in cancer patients both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in one transgene by expressing the non-lymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T-cells. C-MPL signaling activates pathways shared with conventional co-stimulatory and cytokine receptor signaling...
October 27, 2017: Blood
https://www.readbyqxmd.com/read/29078088/inhibition-of-notch-signalling-has-ability-to-alter-the-proximal-and-distal-tcr-signalling-events-in-human-cd3-%C3%AE-%C3%AE-t-cells
#18
Asif A Dar, Sajad A Bhat, Dimpu Gogoi, Abhiram Gokhale, Shubhada V Chiplunkar
The Notch signalling pathway is an important regulator of T cell function and is known to regulate the effector functions of T cells driven by T cell receptor (TCR). However, the mechanism integrating these pathways in human CD3(+) αβ T cells is not well understood. The present study was carried out to investigate how Notch and TCR driven signalling are synchronized in human αβ T cells. Differential expression of Notch receptors, ligands, and target genes is observed on human αβ T cells which are upregulated on stimulation with α-CD3/CD28 mAb...
October 24, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29075267/pd-1-controls-tonic-signaling-and-lymphopenia-induced-proliferation-of-t-lymphocytes
#19
Kristofor K Ellestad, Jiaxin Lin, Louis Boon, Colin C Anderson
Recovery of the T lymphocyte compartment within a lymphopenic host by lymphopenia-induced proliferation (LIP) is regulated by inter- and intraclonal competition for limited resources, including homeostatic cytokines and peptide:MHC (pMHC) complexes with which the TCR can interact at least weakly to yield a tonic signal. Importantly, the process of LIP can synergize with other factors that promote T cell activation to drive inflammatory disease. While reconstitution of the lymphoid compartment of immune deficient Rag(-/-) mice by transfer of wild-type hematopoietic stem cells (HSC) does not generally result in an overt disease phenotype, transfer of HSC deficient in expression of the co-inhibitory molecule PD-1 results in severe systemic autoimmunity driven by newly generated T cells that emerge from the thymus into the periphery and undergo LIP...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29073235/src-family-kinases-negatively-regulate-nfat-signaling-in-resting-human-t-cells
#20
Alan Baer, Winston Colon-Moran, Jinhua Xiang, Jack T Stapleton, Nirjal Bhattarai
T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR) T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs) are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood...
2017: PloS One
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