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https://www.readbyqxmd.com/read/28526413/tcr-crosslinking-promotes-crk-adaptor-protein-binding-to-tyrosine-phosphorylated-cd3%C3%AE-chain
#1
Guangyu Dong, Rachel Kalifa, Pulak Ranjan Nath, Sigal Gelkop, Noah Isakov
T cell antigen receptor (TCR) binding of a peptide antigen presented by antigen-presenting cells (APCs) in the context of surface MHC molecules initiates signaling events that regulate T cell activation, proliferation and differentiation. A key event in the activation process is the phosphorylation of the conserved tyrosine residues within the CD3 chain immunoreceptor tyrosine-based activation motifs (ITAMs), which operate as docking sites for SH2 domain-containing effector proteins. Phosphorylation of the CD3ζ ITAMs renders the CD3 chain capable of binding the ζ-chain associated protein 70 kDa (ZAP70), a protein tyrosine kinase that is essential for T cell activation...
May 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28517553/ifi16-reduced-expression-is-correlated-with-unfavorable-outcome-in-chronic-lymphocytic-leukemia
#2
Pier Paolo Piccaluga, Claudio Agostinelli, Simona Righi, Maria Ciccone, Maria Carla Re, Giuseppina Musumeci, Erica Diani, Caterina Signoretto, Isabella Bon, Ottavio Piccin, Antonio Cuneo, Claudio Tripodo, Cristina Ponti, Donato Zipeto, Santo Landolfo, Davide Gibellini
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Its clinical course is typically indolent; however, based on a series of pathobiological, clinical, genetic, and phenotypic parameters, patient survival varies from less than 5 to more than 20 years. In this paper, we show for the first time that the expression of the interferon-inducible DNA sensor IFI16, a member of the PYHIN protein family involved in proliferation inhibition and apoptosis regulation, is associated with the clinical outcome in CLL...
May 18, 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28465009/crk-adaptor-proteins-regulate-cd3%C3%AE-chain-phosphorylation-and-tcr-cd3-down-modulation-in-activated-t-cells
#3
Guangyu Dong, Rachel Kalifa, Pulak Ranjan Nath, Yael Babichev, Sigal Gelkop, Noah Isakov
T cell receptor (TCR) recognition of a peptide antigen in the context of MHC molecules initiates positive and negative cascades that regulate T cell activation, proliferation and differentiation, and culminate in the acquisition of effector T cell functions. These processes are a prerequisite for the induction of specific T cell-mediated adaptive immune responses. A key event in the activation of TCR-coupled signaling pathways is the phosphorylation of tyrosine residues within the cytoplasmic tails of the CD3 subunits, predominantly CD3ζ...
April 29, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28462950/t-cell-activation-rhogtpase-activating-protein-plays-an-important-role-in-th17-cell-differentiation
#4
Norimasa Tamehiro, Kyoko Nishida, Reiko Yanobu-Takanashi, Motohito Goto, Tadashi Okamura, Harumi Suzuki
T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear. Because TH17 cells contribute to TAGAP-associated autoimmune diseases, we hypothesized that TAGAP plays key roles in the differentiation and/or function of TH17 cells...
May 2, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28448599/simulation-of-the-dynamics-of-primary-immunodeficiencies-in-cd4-t-cells
#5
Gabriel N Teku, Mauno Vihinen
Primary immunodeficiencies (PIDs) form a large and heterogeneous group of mainly rare disorders that affect the immune system. T-cell deficiencies account for about one-tenth of PIDs, most of them being monogenic. Apart from genetic and clinical information, lots of other data are available for PID proteins and genes, including functions and interactions. Thus, it is possible to perform systems biology studies on the effects of PIDs on T-cell physiology and response. To achieve this, we reconstructed a T-cell network model based on literature mining and TPPIN, a previously published core T-cell network, and performed semi-quantitative dynamic network simulations on both normal and T-cell PID failure modes...
2017: PloS One
https://www.readbyqxmd.com/read/28445761/live-cell-super-resolution-reveals-f-actin-and-plasma-membrane-dynamics-at-the-t-cell-synapse
#6
George W Ashdown, Garth L Burn, David J Williamson, Elvis Pandžić, Ruby Peters, Michael Holden, Helge Ewers, Lin Shao, Paul W Wiseman, Dylan M Owen
The cortical actin cytoskeleton has been shown to be critical for the reorganization and heterogeneity of plasma membrane components of many cells, including T cells. Building on previous studies at the T cell immunological synapse, we quantitatively assess the structure and dynamics of this meshwork using live-cell superresolution fluorescence microscopy and spatio-temporal image correlation spectroscopy. We show for the first time, to our knowledge, that not only does the dense actin cortex flow in a retrograde fashion toward the synapse center, but the plasma membrane itself shows similar behavior...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28415650/a-highly-conserved-redox-active-mx-2-cwx-6-r-motif-regulates-zap70-stability-and-activity
#7
Christoph Thurm, Mateusz P Poltorak, Elisa Reimer, Melanie M Brinkmann, Lars Leichert, Burkhart Schraven, Luca Simeoni
ζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412730/the-long-noncoding-rna-trerna-decreases-dna-damage-and-is-associated-with-poor-response-to-chemotherapy-in-chronic-lymphocytic-leukemia
#8
Cecelia R Miller, Amy S Ruppert, Sydney Fobare, Timothy L Chen, Chaomei Liu, Amy Lehman, James S Blachly, Xiaoli Zhang, David M Lucas, Michael R Grever, Martin S Tallman, Ian W Flinn, Laura Z Rassenti, Thomas J Kipps, Deepa Sampath, Kevin R Coombes, Erin K Hertlein
The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28333124/bap31-is-involved-in-t-cell-activation-through-tcr-signal-pathways
#9
Kunwei Niu, Jialin Xu, Yuhua Cao, Yue Hou, Mu Shan, Yanqing Wang, Yang Xu, Mingyi Sun, Bing Wang
BAP31 is a ubiquitously expressed endoplasmic reticulum (ER) membrane protein. The functions of BAP31 in the immune system have not been investigated due to the lack of animal models. Therefore we created a BAP31 conditional knockdown mouse by performing a knockdown of BAP31 in the thymus. In doing so, we demonstrate that the maturation of T cells is normal but the number of T cells is less in the thymus of the knockout mouse. In addition, the spleen and lymph nodes of peripheral immune organs contained a lesser proportion of the mature T cells in the thymus specific BAP31 knockout mice...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28286257/grouper-epinephelus-coioides-tcr-signaling-pathway-was-involved-in-response-against-cryptocaryon-irritans-infection
#10
Ze-Xiang Li, Yan-Wei Li, Shun Xu, Yang Xu, Ze-Quan Mo, Xue-Ming Dan, Xiao-Chun Luo
T cell activation is a complicated process accompanying with the activation of T cell receptor (TCR) signaling pathway, which is not well described in teleost fish. The initiation of this pathway depends on the interaction of membrane TCR co-receptors (e.g. CD4/8, CD3 and CD45) and a series of cytoplasmic protein tyrosine kinases (e.g. Lck, Fyn and ZAP70). Cyptocaryon irritans is a ciliate pathogen of marine fish white spot disease causing huge economic lost in marine aquaculture. This parasite can infect fish gill and skin and is considered to be a good pathogen model for fish gill and skin mucosal immunity...
May 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28266732/pharmacogenetics-of-steroid-responsive-acute-graft-versus-host-disease
#11
Mukta Arora, Daniel J Weisdorf, Ryan M Shanley, Bharat Thyagarajan
Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy...
May 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/28235866/rab11-fip3-regulation-of-lck-endosomal-traffic-controls-tcr-signal-transduction
#12
Jérôme Bouchet, Iratxe Del Río-Iñiguez, Elena Vázquez-Chávez, Rémi Lasserre, Sonia Agüera-González, Céline Cuche, Mary W McCaffrey, Vincenzo Di Bartolo, Andrés Alcover
The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3)...
February 24, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28216435/morpholino-based-correction-of-hypomorphic-zap70-mutation-in-an-adult-with-combined-immunodeficiency
#13
Christina Gavino, Marija Landekic, Jibin Zeng, Ning Wu, Sungmi Jung, Ming-Chao Zhong, Alexis Cohen-Blanchet, Mélanie Langelier, Odile Neyret, Duncan Lejtenyi, Claudia Rochefort, Judith Cotton-Montpetit, Christine McCusker, Bruce Mazer, André Veillette, Donald C Vinh
No abstract text is available yet for this article.
May 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28164634/cd38-expression-and-variation-as-a-prognostic-factor-chronic-lymphocytic-leukemia
#14
Mesude Falay, Funda Ceran, Ahmet K Gunes, Simten Dagdas, Meltem Ayli, Gulsum Ozet
BACKGROUND: In this study, we aimed to determine a cutoff level for CD38 that would aid us in identifying chronic lymphocytic leukemia patients in need of early therapy and predicting patients at sufficiently low risk who would likely exhibit a rapid improvement; we also aimed to find out if CD38 expression would show variability during disease course and determine the extent of CD38 expression. METHODS: 124 patients were diagnosed with CLL. CD38 and ZAP-70 expression levels were measured with four color flowcytometry...
July 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28159798/destabilizing-the-autoinhibitory-conformation-of-zap70-induces-up-regulation-of-inhibitory-receptors-and-t-cell-unresponsiveness
#15
Lih-Yun Hsu, Debra A Cheng, Yiling Chen, Hong-Erh Liang, Arthur Weiss
Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII(+) thymocytes and in increased thymic and peripheral T regulatory cells...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28124082/novel-compound-heterozygous-mutations-in-zap70-in-a-chinese-patient-with-leaky-severe-combined-immunodeficiency-disorder
#16
Qing Liu, Yan-Ping Wang, Qiao Liu, Qin Zhao, Xue-Mei Chen, Xiu-Hong Xue, Li-Na Zhou, Yuan Ding, Xue-Mei Tang, Xiao-Dong Zhao, Zhi-Yong Zhang
In humans, the complete lack of tyrosine kinase ZAP70 function results in combined immunodeficiency (CID), with abnormal thymic development and defective T cell receptor (TCR) signaling of peripheral T cells, characterized by the selective absence of CD8(+) T cells. So far, 15 unique ZAP70 mutations have been identified in approximately 20 patients with CID, with variable clinical presentations. Herein, we report the first case from China of novel compound heterozygous mutations in ZAP70 (c.598-599delCT, p...
April 2017: Immunogenetics
https://www.readbyqxmd.com/read/28115735/leukemia-cell-proliferation-and-disease-progression-in-patients-with-early-stage-chronic-lymphocytic-leukemia
#17
E J Murphy, D S Neuberg, L Z Rassenti, G Hayes, R Redd, C Emson, K Li, J R Brown, W G Wierda, S Turner, A W Greaves, C S Zent, J C Byrd, C McConnel, J Barrientos, N Kay, M K Hellerstein, N Chiorazzi, T J Kipps, K R Rai
The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo (2)H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28092460/a-three-dimensional-lymphatic-endothelial-cell-tube-formation-assay-to-identify-novel-kinases-involved-in-lymphatic-vessel-remodeling
#18
T Jessica Gambino, Steven P Williams, Carol Caesar, Daniel Resnick, Cameron J Nowell, Rae H Farnsworth, Marc G Achen, Steven A Stacker, Tara Karnezis
The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes...
January 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/27942588/tumor-infiltrating-lymphocytes-are-dynamically-desensitized-to-antigen-but-are-maintained-by-homeostatic-cytokine
#19
Bijan Boldajipour, Amanda Nelson, Matthew F Krummel
T cells that enter tumors are largely tolerized, but how that process is choreographed and how the ensuing "dysfunctional" tumor-infiltrating lymphocytes (TILs) are maintained are poorly understood and are difficult to assess in spontaneous disease. We exploited an autochthonous model of breast cancer for high-resolution imaging of the early and later stages of tumor residence to understand the relationships between cellular behaviors and cellular phenotypes. "Dysfunctional" differentiation began within the first days of tumor residence with an initial phase in which T cells arrest, largely on tumor-associated macrophages...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27869819/a-cycle-of-zap70-kinase-activation-and-release-from-the-tcr-amplifies-and-disperses-antigenic-stimuli
#20
Zachary B Katz, Lucie Novotná, Amy Blount, Björn F Lillemeier
Cell-surface-receptor pathways amplify weak, rare and local stimuli to induce cellular responses. This task is accomplished despite signaling components that segregate into nanometer-scale membrane domains. Here we describe a 'catch-and-release' mechanism that amplified and dispersed stimuli by releasing activated kinases from receptors lacking intrinsic catalytic activity. Specifically, we discovered a cycle of recruitment, activation and release for Zap70 kinases at phosphorylated T cell antigen receptors (TCRs)...
January 2017: Nature Immunology
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