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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/29142313/effects-of-exosome-on-the-activation-of-cd4-t-cells-in-rhesus-macaques-a-potential-application-for-hiv-latency-reactivation
#3
Xiaowu Hong, Blake Schouest, Huanbin Xu
Exosomes are small extracellular vesicles (EVs), released by a wide variety of cell types, carry donor origin-proteins, cytokines, and nucleic acids, transport these cargos to adjacent or distant specific recipient cells, and thereby regulate gene expression and activation of target cells. In this study, we isolated and identified exosomes in rhesus macaques, and investigated their effects on cell tropism and activation, especially their potential to reactivate HIV latency. The results indicated that plasma-derived exosomes preferentially fuse to TCR-activated T cells and autologous parent cells...
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/29123516/avidity-and-bystander-suppressive-capacity-of-human-regulatory-t-cells-expressing-de-novo-autoreactive-t-cell-receptors-in-type-1-diabetes
#8
Wen-I Yeh, Howard R Seay, Brittney Newby, Amanda L Posgai, Filipa Botelho Moniz, Aaron Michels, Clayton E Mathews, Jeffrey A Bluestone, Todd M Brusko
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29122757/crispr-mediated-tcr-replacement-generates-superior-anticancer-transgenic-t-cells
#9
Mateusz Legut, Garry Dolton, Afsar Ali Mian, Oliver Ottmann, Andrew Sewell
Adoptive transfer of T-cells genetically modified to express a cancer-specific T-cell receptor (TCR) has shown significant therapeutic potential for both hematological and solid tumors. However, a major issue of transducing T-cells with a transgenic TCR is the pre-existing expression of TCRs in the recipient cells. These endogenous TCRs compete with the transgenic TCR for surface expression and allow mixed dimer formation. Mixed dimers, formed by mispairing between the endogenous and transgenic TCRs, may harbor autoreactive specificities...
November 9, 2017: Blood
https://www.readbyqxmd.com/read/29111199/density-dependent-re-tuning-of-autoreactive-t-cells-alleviates-their-pathogenicity-in-a-lymphopenic-environment
#10
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
#11
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/29106983/gabab-receptor-subtypes-differentially-regulate-thalamic-spindle-oscillations
#12
REVIEW
Daniel Ulrich, Txomin Lalanne, Martin Gassmann, Bernhard Bettler
Following the discovery of GABAB receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABAB receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABAB1a, GABAB1b and GABAB2 form two heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors that can associate with tetramers of auxiliary KCTD (K(+) channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABAB(1b,2) receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABAB(1a,2) receptors function as heteroreceptors and inhibit glutamate release...
October 26, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29105157/reduced-numbers-of-mature-medullary-thymic-epithelial-cells-in-skg-mice
#13
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/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/29100943/the-avidity-of-cross-reactive-virus-specific-t-cells-for-their-viral-and-allogeneic-epitopes-is-variable-and-depends-on-epitope-expression
#15
Heleen van den Heuvel, Kirstin M Heutinck, Ellen M W van der Meer-Prins, Marry E I Franke-van Dijk, Paula P M C van Miert, Xiaoqian Zhang, Ineke J M Ten Berge, Frans H J Claas
Virus-specific T cells can recognize allogeneic HLA (allo-HLA) through cross-reactivity of their T-cell receptor (TCR). In a transplantation setting, such allo-HLA cross-reactivity may contribute to harmful immune responses towards the allograft, provided that the cross-reactive T cells get sufficiently activated upon recognition of the allo-HLA. An important determinant of T-cell activation is TCR avidity, which to date, has remained largely unexplored for allo-HLA-cross-reactive virus-specific T cells. For this purpose, cold target inhibition assays were performed using allo-HLA-cross-reactive virus-specific memory CD8(+) T-cell clones as responders, and syngeneic cells loaded with viral peptide and allogeneic cells as hot (radioactively-labeled) and cold (non-radioactively-labeled) targets...
October 31, 2017: Human Immunology
https://www.readbyqxmd.com/read/29100330/protective-cellular-immunity-generated-by-cross-presenting-recombinant-overlapping-peptide-proteins
#16
Lili Cai, Jianbo Zhang, Renying Zhu, Weixing Shi, Xiaobing Xia, Mark Edwards, William Finch, Anthony Coombs, Ju Gao, Kangwen Chen, Sophie Owen, Shisong Jiang, Wenshu Lu
Priming of naive CD8(+) and CD4(+) T cells by dendritic cells (DCs) requires effective antigen presentation on both MHC class I and II molecules. We have developed a novel technology to use recombinant overlapping peptides (ROP) that stimulate both CD8(+) and CD4(+) T cell immune responses. The single chain protein of a ROP is made up of overlapping peptides linked by the target sequence (LRMK) for cathepsin S, a protease found in the endosomes of DCs. We designed synthetic genes encoding ROPs derived from ovalbumin (OVA), tuberculosis protein (CFP10-ESAT6), human papilloma virus (HPV) protein (E7) and survivin, a protein commonly over-expressed in tumour cells...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100058/activation-induced-foxp3-isoform-profile-in-peripheral-cd4-t-cells-is-associated-with-coronary-artery-disease
#17
Anna K Lundberg, Lena Jonasson, Göran K Hansson, Reiner K W Mailer
BACKGROUND AND AIMS: The expression of FOXP3 isoforms affects regulatory T (Treg) cell function. Reduced Treg cell function has been associated with coronary artery disease (CAD). However, alternative splicing of FOXP3 in CAD has not been investigated. METHODS: FOXP3 splice variants and IL17A transcripts in peripheral blood mononuclear cells from stable CAD patients and healthy controls were quantified, and FOXP3 isoform expression in response to T cell receptor (TCR) stimulation or LDL was analyzed by flow cytometry...
October 20, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/29097726/palmitate-inhibits-arthritis-by-inducing-t-bet-and-gata-3-mrna-degradation-in-inkt-cells-via-ire1%C3%AE-dependent-decay
#18
Jae Sung Ko, Jae Moon Koh, Jae-Seon So, Yoon Kyung Jeon, Hye Young Kim, Doo Hyun Chung
Long chain fatty acids (LCFAs) exert pro-inflammatory effects in vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors in iNKT cells. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-γ production and reduced gata-3 and t-bet transcript levels in iNKT cells during TCR-mediated activation. In iNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1α RNase...
November 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29083415/encoding-optical-control-in-lck-kinase-to-quantitatively-investigate-its-activity-in-live-cells
#19
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
#20
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
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