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TCR signaling

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https://www.readbyqxmd.com/read/28747670/pkc-%C3%B1-is-dispensable-for-ox40l-induced-tcr-independent-treg-proliferation-but-contributes-by-enabling-il-2-production-from-effector-t-cells
#1
Khaled Alharshawi, Alejandra Marinelarena, Prabhakaran Kumar, Osama El-Sayed, Palash Bhattacharya, Zuoming Sun, Alan L Epstein, Ajay V Maker, Bellur S Prabhakar
We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3(+) Tregs, but not Foxp3(-) effector T-cells (Teff), when CD4(+) T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4(+) T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28746867/tcr-signal-quality-modulates-fate-decisions-of-single-cd4-t-cells-in-a-probabilistic-manner
#2
Yi-Li Cho, Michael Flossdorf, Lorenz Kretschmer, Thomas Höfer, Dirk H Busch, Veit R Buchholz
To what extent the lineage decisions of activated CD4(+) T cells are determined by the quality of T cell receptor (TCR) ligation is incompletely understood. Here, we show that individual T cells expressing identical TCRs take highly variable fate decisions despite binding the same ligand. We identify a mathematical model that correctly captures this probabilistic behavior and allows one to formalize changes in TCR signal quality-due to cognate versus altered peptide ligation-as changes of lineage-specific proliferation and differentiation rates...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28742882/t-cell-intrinsic-tlr2-stimulation-promotes-il-10-expression-and-suppressive-activity-by-cd45rbhi-t-cells
#3
Janice C Jun, Mark B Jones, Douglas M Oswald, Edward S Sim, Amruth R Jonnalagadda, Lori S C Kreisman, Brian A Cobb
While Toll-like receptors (TLRs) represent one of the best characterized innate immune pathways, evidence suggests that TLRs are not restricted to innate leukocytes and some epithelial cells, but are also expressed in T cells. Specifically, published evidence focusing on FoxP3+ regulatory T cells demonstrate that they express functional TLR2, which is already known among the TLR family for its association with immune suppression; however, little is known about the relationship between T cell-intrinsic TLR2 binding and cytokine production, T cell differentiation, or T cell receptor (TCR) stimulation...
2017: PloS One
https://www.readbyqxmd.com/read/28740495/the-affinity-of-elongated-membrane-tethered-ligands-determines-potency-of-t-cell-receptor-triggering
#4
Bing-Mae Chen, Mohammad Ameen Al-Aghbar, Chien-Hsin Lee, Tien-Ching Chang, Yu-Cheng Su, Ya-Chen Li, Shih-En Chang, Chin-Chuan Chen, Tsai-Hua Chung, Yuan-Chun Liao, Chau-Hwang Lee, Steve R Roffler
T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I and II pMHC molecules...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28735895/a-phosphosite-within-the-sh2-domain-of-lck-regulates-its-activation-by-cd45
#5
Adam H Courtney, Jeanine F Amacher, Theresa A Kadlecek, Marianne N Mollenauer, Byron B Au-Yeung, John Kuriyan, Arthur Weiss
The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck...
July 11, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28733484/cutting-edge-cd3-itam-diversity-is-required-for-optimal-tcr-signaling-and-thymocyte-development
#6
Matthew L Bettini, Po-Chein Chou, Clifford S Guy, Thomas Lee, Kate M Vignali, Dario A A Vignali
For the αβ or γδTCR chains to integrate extracellular stimuli into the appropriate intracellular cellular response, they must use the 10 ITAMs found within the CD3 subunits (CD3γε, CD3δε, and ζζ) of the TCR signaling complex. However, it remains unclear whether each specific ITAM sequence of the individual subunit (γεδζ) is required for thymocyte development or whether any particular CD3 ITAM motif is sufficient. In this article, we show that mice utilizing a single ITAM sequence (γ, ε, δ, ζa, ζb, or ζc) at each of the 10 ITAM locations exhibit a substantial reduction in thymic cellularity and limited CD4(-)CD8(-) (double-negative) to CD4(+)CD8(+) (double-positive) maturation because of low TCR expression and signaling...
July 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28716889/cytokines-transcription-factors-and-the-initiation-of-t-cell-development
#7
Hiroyuki Hosokawa, Ellen V Rothenberg
Multipotent blood progenitor cells migrate into the thymus and initiate the T-cell differentiation program. T-cell progenitor cells gradually acquire T-cell characteristics while shedding their multipotentiality for alternative fates. This process is supported by extracellular signaling molecules, including Notch ligands and cytokines, provided by the thymic microenvironment. T-cell development is associated with dynamic change of gene regulatory networks of transcription factors, which interact with these environmental signals...
July 17, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28714979/translation-is-actively-regulated-during-the-differentiation-of-cd8-effector-t-cells
#8
Koichi Araki, Masahiro Morita, Annelise G Bederman, Bogumila T Konieczny, Haydn T Kissick, Nahum Sonenberg, Rafi Ahmed
Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8(+) effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal-expansion phase, followed by inhibition of the translation of those transcripts when the CD8(+) Teff cells stopped dividing just before the contraction phase...
July 17, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28713387/human-cd6-down-modulation-following-t-cell-activation-compromises-lymphocyte-survival-and-proliferative-responses
#9
Esther Carrasco, Cristina Escoda-Ferran, Núria Climent, Cristina Miró-Julià, Inês T Simões, Mario Martínez-Florensa, Adelaida Sarukhan, Esther Carreras, Francisco Lozano
Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen-presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T cells under different TCR-ligation conditions leads to surface downregulation of CD6 expression. This phenomenon was (i) concomitant to increased levels of soluble CD6 (sCD6) in culture supernatants, (ii) partially reverted by protease inhibitors, (iii) not associated to CD6 mRNA down-regulation, and (iv) reversible by stimulus removal...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28708252/redundant-and-regulatory-roles-for-tlrs-in-leishmania-infection
#10
REVIEW
Prashant Chauhan, Divanshu Shukla, Debprasad Chattopadhyay, Bhaskar Saha
Toll-like receptors (TLRs) are germ-line encoded, non-clonal innate immune receptors, which are often the first receptors to recognize the molecular patterns on pathogens. Therefore, the immune response initiated by TLRs does have far-reaching consequences on the outcome of an infection. As soon as the cell surface TLRs and other receptors recognize a pathogen, the pathogen is phagocytosed. Inclusion of TLRs in the phagosome results in quicker phagosomal maturation and stronger adaptive immune response, as TLRs influence costimulatory molecules expression and determinant selection by MHC class-II and by MHC class-I for cross-presentation...
July 14, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28707108/clinical-and-biological-insights-from-the-university-of-california-san-francisco-prospective-and-longitudinal-cohort
#11
Bryan S Benn, Zoe Lehman, Sharon A Kidd, Melissa Ho, Sara Sun, Joris Ramstein, Nicholas K Arger, Christine P Nguyen, Robert Su, Antonio Gomez, Jeffrey M Gelfand, Laura L Koth
INTRODUCTION: Sarcoidosis is a systemic inflammatory disease characterized by non-necrotizing granulomas in involved organs, most commonly the lung. Description of patient characteristics in the Western United States is limited. Furthermore, blood-based measures that relate to clinical sarcoidosis phenotypes are lacking. We present an analysis of a prospective, longitudinal sarcoidosis cohort at a Northern Californian academic medical center. METHODS: We enrolled 126 sarcoidosis subjects and 64 healthy controls and recorded baseline demographic and clinical characteristics...
July 13, 2017: Lung
https://www.readbyqxmd.com/read/28699640/lfa-1-activates-focal-adhesion-kinases-fak1-pyk2-to-generate-lat-grb2-skap1-complexes-that-terminate-t-cell-conjugate-formation
#12
Monika Raab, Yuning Lu, Karsten Kohler, Xin Smith, Klaus Strebhardt, Christopher E Rudd
Lymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering. Although increased affinity mediates adhesion, LFA-1 cross-linking induced the association and activation of the protein-tyrosine kinases FAK1/PYK1 that phosphorylated LAT selectively on a single Y-171 site for the binding to adaptor complex GRB-2-SKAP1...
July 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28699257/effects-of-ochratoxin-a-on-er-stress-mapk-signaling-pathway-and-autophagy-of-kidney-and-spleen-in-pigs
#13
Fang Gan, Lili Hou, Yajiao Zhou, Yunhuan Liu, Da Huang, Xingxiang Chen, Kehe Huang
Ochratoxin A (OTA), a worldwide mycotoxin found in food and feeds, is a potent nephrotoxin and immunotoxin in animals and humans. This research was conducted to evaluate whether endoplasmic reticulum (ER) stress, MAPK signaling pathway and autophagy were induced by OTA in kidney and spleen of pigs. Twenty-seven crossbred pigs randomly allocated to 3 groups were fed for 42 days ad libitum a basal diet without (Con group, 0.00 μg OTA/kg) and with supplementation of OTA at 400 (OTA-L group) and 800 μg/kg (OTA-H group)...
July 12, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28697966/themis-two-models-different-thresholds
#14
REVIEW
Seeyoung Choi, Richard Cornall, Renaud Lesourne, Paul E Love
THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR), but the mechanistic underpinnings of THEMIS function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling...
July 8, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28696283/suboptimal-t-cell-receptor-signaling-compromises-protein-translation-ribosome-biogenesis-and-proliferation-of-mouse-cd8-t-cells
#15
Thomas C J Tan, John Knight, Thomas Sbarrato, Kate Dudek, Anne E Willis, Rose Zamoyska
Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes...
July 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28694326/genomic-analysis-of-220-ctcls-identifies-a-novel-recurrent-gain-of-function-alteration-in-rltpr-p-q575e
#16
Joonhee Park, Jingyi Yang, Alexander T Wenzel, Akshaya Ramachandran, Wung J Lee, Jay C Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L Mendillo, Jeffrey N Savas, Titus J Boggon, Jaehyuk Choi
Cutaneous T cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early stage disease, lesions are limited to the skin, but in later stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-Kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA-splicing (U2AF1), T cell receptor signaling (PTPRN2, RLTPR), and T cell differentiation (RARA)...
July 10, 2017: Blood
https://www.readbyqxmd.com/read/28694325/tcr-cxcr4-signaling-stabilizes-cytokine-mrna-transcripts-via-a-prex1-rac1-pathway-implications-for-ctcl
#17
Kimberly N Kremer, Brittney A Dinkel, Rosalie M Sterner, Douglas G Osborne, Dragan Jevremovic, Karen E Hedin
As with many immunopathologically-driven diseases, the malignant T cells of cutaneous T cell lymphomas (CTCL), such as Sezary Syndrome, display aberrant cytokine secretion patterns that contribute to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCL. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling...
July 10, 2017: Blood
https://www.readbyqxmd.com/read/28687658/the-effect-of-inhibitory-signals-on-the-priming-of-drug-hapten-specific-t-cells-that-express-distinct-v%C3%AE-receptors
#18
Andrew Gibson, Lee Faulkner, Maike Lichtenfels, Monday Ogese, Zaid Al-Attar, Ana Alfirevic, Philipp R Esser, Stefan F Martin, Munir Pirmohamed, B Kevin Park, Dean J Naisbitt
Drug hypersensitivity involves the activation of T cells in an HLA allele-restricted manner. Because the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell-priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vβ subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses...
July 7, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28681958/bj-2266-ameliorates-experimental-autoimmune-encephalomyelitis-through-down-regulation-of-the-jak-stat-signaling-pathway
#19
Zhiwei You, Maheshwor Timilshina, Byeong-Seon Jeong, Jae-Hoon Chang
CD4(+) T cells differentiate into distinct effector subsets upon antigenic stimulation. Cytokines, and micro-environmental factors present during T-cell priming, direct differentiation of naïve CD4(+) T cells into pro-inflammatory Th1 and Th17 cells. From extensive screening of 2,4,5-trimethylpyridin-3-ol derivatives with various functional groups at C(6)-position, BJ-2266, a 6-thioureido-derivative, showed potent inhibitory activity on in vitro T helper (Th)-cell differentiation. This compound inhibited IFN-γ and IL-17 production from polyclonal CD4(+) T cells and ovalbumin (OVA)-specific CD4(+) T cells that were activated by T-cell receptor (TCR) engagement...
July 6, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28681703/hybrid-approach-to-model-the-spatial-regulation-of-t-cell-responses
#20
Anass Bouchnita, Gennady Bocharov, Andreas Meyerhans, Vitaly Volpert
BACKGROUND: Moving from the molecular and cellular level to a multi-scale systems understanding of immune responses requires the development of novel approaches to integrate knowledge and data from different biological levels into mechanism-based integrative mathematical models. The aim of our study is to present a methodology for a hybrid modelling of immunological processes in their spatial context. METHODS: A two-level hybrid mathematical model of immune cell migration and interaction integrating cellular and organ levels of regulation for a 2D spatial consideration of idealized secondary lymphoid organs is developed...
June 21, 2017: BMC Immunology
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