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https://www.readbyqxmd.com/read/29720981/the-neutral-sphingomyelinase-2-is-required-to-polarize-and-sustain-t-cell-receptor-signaling
#1
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/29695768/association-between-single-nucleotide-polymorphisms-and-adverse-events-in-nivolumab-treated-non-small-cell-lung-cancer-patients
#2
Sander Bins, Edwin A Basak, Samira El Bouazzaoui, Stijn L W Koolen, E Oomen-de Hoop, Cor H van der Leest, Astrid A M van der Veldt, Stefan Sleijfer, Reno Debets, Ron H N van Schaik, Joachim G J V Aerts, Ron H J Mathijssen
BACKGROUND: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. METHODS: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i...
April 26, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29686683/high-affinity-ligands-can-trigger-t-cell-receptor-signaling-without-cd45-segregation
#3
Mohammad Ameen Al-Aghbar, Yeh-Shiu Chu, Bing-Mae Chen, Steve R Roffler
How T cell receptors (TCRs) are triggered to start signaling is still not fully understood. It has been proposed that segregation of the large membrane tyrosine phosphatase CD45 from engaged TCRs initiates signaling by favoring phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic domains of CD3 molecules. However, whether CD45 segregation is important to initiate triggering is still uncertain. We examined CD45 segregation from TCRs engaged to anti-CD3 scFv with high or low affinity and with defined molecular lengths on glass-supported lipid bilayers using total internal reflection microscopy...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29684201/dysregulation-of-epstein-barr-virus-infection-in-hypomorphic-zap70-mutation
#4
Akihiro Hoshino, Takehiro Takashima, Kenichi Yoshida, Akira Morimoto, Yuta Kawahara, Tzu-Wen Yeh, Tsubasa Okano, Motoi Yamashita, Noriko Mitsuiki, Kohsuke Imai, Takashi Sakatani, Atsuko Nakazawa, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Tomohiro Morio, Hirokazu Kanegane
Background: Some patients with genetic defects develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD)/lymphoma as the main feature. Hypomophic mutations can cause different clinical and laboratory manifestations from null mutations in the same genes. Methods: We sought to describe the clinical and immunologic phenotype of a 21-month-old boy having EBV-associated LPD who was in good health till then. A genetic and immunologic analysis was performed...
April 19, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29589978/zap70-expression-enhances-chemokine-driven-chronic-lymphocytic-leukemia-cell-migration-and-arrest-by-valency-regulation-of-integrins
#5
Julia M Laufer, Ruth Lyck, Daniel F Legler
The ζ-associated protein of 70 kDa (ZAP70) is expressed in the aggressive form of B-cell chronic lymphocytic leukemia (CLL). Moreover, the integrin very late antigen (VLA)-1 is highly expressed on subtypes of CLL that are associated with high proliferation rates in the lymph node context. We herein identify a critical role for ZAP70 in chemokine-mediated, inside-out signaling to integrins in trisomy 12 carrying Ohio State University-CLL cell lines derived from a patient with previously treated CLL. We found that ZAP70-positive CLL cells migrated significantly better toward ligands of the lymph node homing chemokine receptors CCR7 and CXCR4 compared with ZAP70-negative cells...
March 28, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29589904/engineering-a-dual-small-molecule-gated-zap70-switch-in-t-cells
#6
Nicole M L Wong, Wilson W Wong
T cells expressing tumor-specific T cell receptors are promising cancer therapeutic agents, but safety control switches are needed to manage potential side effects arising from overactivity. Here, we present the first dual small molecule-gated ZAP70 signaling switch for the regulation of T cell activity. We show that when an analogue-sensitive ZAP70 allele is fused to the engineered ligand binding domain of the estrogen receptor, ERT2 , its activity can be upregulated to an extent by a metabolite of an FDA-approved tamoxifen, 4-hydroxy-tamoxifen, and downregulated by an ATP analogue, 3-MB-PP1...
April 20, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29567540/silencing-zap70-prevents-hsp65-induced-reverse-cholesterol-transport-and-nf-%C3%AE%C2%BAb-activation-in-t-cells
#7
Jing Hu, Tiantian Luo, Dan Xi, Kai Guo, Lu Hu, Jinzhen Zhao, Si Chen, Zhigang Guo
T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development. The ζ chain-associated 70-kDa protein (ZAP70) is sequentially activated in response to TCR engagement and serves as a critical component of the TCR signaling pathway, which is essential for T cell activation. However, some roles of ZAP70 have not been fully elucidated. In the present study, we analyzed the effects of ZAP70 on the cholesterol efflux rate, nuclear factor κB (NF-κB) activation and cell proliferation in T cells...
March 19, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29479062/distinct-roles-for-phosphoinositide-3-kinases-%C3%AE-and-%C3%AE-in-malignant-b-cell-migration
#8
Ahmed Y Ali, Xun Wu, Nour Eissa, Sen Hou, Jean-Eric Ghia, Thomas T Murooka, Versha Banerji, James B Johnston, Francis Lin, Spencer B Gibson, Aaron J Marshall
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors...
January 31, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29456532/a-stretch-of-negatively-charged-amino-acids-of-linker-for-activation-of-t-cell-adaptor-has-a-dual-role-in-t-cell-antigen-receptor-intracellular-signaling
#9
Mikel M Arbulo-Echevarria, Isaac Narbona-Sánchez, Cecilia M Fernandez-Ponce, Inmaculada Vico-Barranco, Mª Dolores Rueda-Ygueravide, Michael L Dustin, Arkadiusz Miazek, Mª Carmen Duran-Ruiz, Francisco García-Cózar, Enrique Aguado
The adaptor protein linker for activation of T cells (LAT) has an essential role transducing activatory intracellular signals coming from the TCR/CD3 complex. Previous reports have shown that upon T-cell activation, LAT interacts with the tyrosine kinase Lck, leading to the inhibition of its kinase activity. LAT-Lck interaction seemed to depend on a stretch of negatively charged amino acids in LAT. Here, we have substituted this segment of LAT between amino acids 113 and 126 with a non-charged segment and expressed the mutant LAT (LAT-NIL) in J...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29410283/new-insights-into-the-vav1-activation-cycle-in-lymphocytes
#10
María Barreira, Sonia Rodríguez-Fdez, Xosé R Bustelo
Vav1 is a hematopoietic-specific Rho GDP/GTP exchange factor and signaling adaptor. Although these activities are known to be stimulated by direct Vav1 phosphorylation, little information still exists regarding the regulatory layers that influence the overall Vav1 activation cycle. Using a collection of cell models and activation-mimetic Vav1 mutants, we show here that the dephosphorylated state of Vav1 in nonstimulated T cells requires the presence of a noncatalytic, phospholipase Cγ1-Slp76-mediated inhibitory pathway...
May 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29316456/disease-characteristics-and-clinical-outcomes-in-patients-aged-less-than-40-with-chronic-lymphocytic-leukemia
#11
Bartlomiej M Getta, Sean Devlin, Jae H Park, Martin S Tallman, Ellin Berman
Outcomes in very young CLL patients (age ≤40) are not well characterized. We compared 71 consecutive patients aged ≤40 with 142 "older" matched patients >40 from our institution and used SEER database as an independent comparison group. Patients in the two age groups were diagnosed at similar Rai stage. At diagnosis, very young patients had a similar rate of adverse cytogenetics, IGHV mutation and ZAP70 expression and had lower beta-2-microglobulin and a lower incidence of second malignancies...
February 2018: Leukemia Research
https://www.readbyqxmd.com/read/29202478/%C3%AE-%C3%AE-tcr-recruits-the-syk-pi3k-axis-to-drive-proinflammatory-differentiation-program
#12
Ryunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, Harumi Suzuki
γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29196709/lck-is-a-relevant-target-in-chronic-lymphocytic-leukaemia-cells-whose-expression-variance-is-unrelated-to-disease-outcome
#13
Kathleen J Till, John C Allen, Fatima Talab, Ke Lin, David Allsup, Lynn Cawkwell, Alison Bentley, Ingo Ringshausen, Andrew D Duckworth, Andrew R Pettitt, Nagesh Kalakonda, Joseph R Slupsky
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29146547/a-gene-module-associated-with-dysregulated-tcr-signaling-pathways-in-cd4-t-cell-subsets-in-rheumatoid-arthritis
#14
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/29125235/comparison-of-the-mrna-expression-profile-of-b-cell-receptor-components-in-normal-cd5-high-b-lymphocytes-and-chronic-lymphocytic-leukemia-a-key-role-of-zap70
#15
COMPARATIVE STUDY
Aleena A Gladkikh, Daria M Potashnikova, Victor Tatarskiy, Margarita Yastrebova, Alvina Khamidullina, Natasha Barteneva, Ivan Vorobjev
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils...
December 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29105157/reduced-numbers-of-mature-medullary-thymic-epithelial-cells-in-skg-mice
#16
R Engelmann, A Biemelt, A Johl, D Kuthning, B Müller-Hilke
Attenuated T cell receptor (TCR) signalling 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...
January 2018: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/29075057/evaluation-of-interleukin-9-expression-as-a-potential-therapeutic-target-in-chronic-lymphocytic-leukemia-in-a-cohort-of-egyptian-patients
#17
Hadeer A Abbassy, Reham A Aboelwafa, Omar M Ghallab
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that has a highly variable clinical course. Genomic features as zeta-chain-associated protein kinase 70 (ZAP70) expression and CD38 expression provide further differentiation of disease prognosis. Extensive studies have confirmed the oncogenic activities of IL-9 in lymphoma. The aim of the current study was to investigate the contribution of IL-9 expression to the pathogenesis of CLL and its correlation to other prognostic parameters. This study was conducted on 80 patients at diagnosis with CLL and 80 healthy controls...
December 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28965845/the-immune-signaling-adaptor-lat-contributes-to-the-neuroanatomical-phenotype-of-16p11-2-bp2-bp3-cnvs
#18
Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C Collins, Konstantin Popadin, Camille S Bonnet, Giuliana Giannuzzi, Anne M Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond
Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28930697/overexpression-of-muc1-and-genomic-alterations-in-its-network-associate-with-prostate-cancer-progression
#19
Xiaozeng Lin, Yan Gu, Anil Kapoor, Fengxiang Wei, Tariq Aziz, Diane Ojo, Yanzhi Jiang, Michael Bonert, Bobby Shayegan, Huixiang Yang, Khalid Al-Nedawi, Pierre Major, Damu Tang
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN(-/-) mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort...
November 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28912049/two-novel-mutations-in-zap70-gene-that-result-in-human-immunodeficiency
#20
Beatriz Adriana Llamas-Guillén, Nina Pastor, Gabriela López-Herrera, Maria Edith González-Serrano, Lucero Valenzuela-Vázquez, Maria Elena Bravo-Adame, Tania Maria Villanueva-Cabello, Paul Gaytán, Jorge Yañez, Ivan Martinez-Duncker, Miguel Ruiz-Fernández, André Veillette, Sara Elva Espinosa-Padilla, Mario Ernesto Cruz-Munoz
No abstract text is available yet for this article.
October 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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