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https://www.readbyqxmd.com/read/29792863/identification-of-immunodominant-cd8-epitope-in-the-stalk-domain-of-influenza-b-viral-hemagglutinin
#1
Abenaya Muralidharan, Caroline Gravel, Amparo Duran, Louise Larocque, Changgui Li, Adrian Zetner, Gary Van Domselaar, Lisheng Wang, Xuguang Li
Human infections by type B influenza virus constitute about 25% of all influenza cases. The viral hemagglutinin is comprised of two subunits, HA1 and HA2. While HA1 is constantly evolving in an unpredictable fashion, the HA2 subunit is highly conserved, making it a potential candidate for a universal vaccine. However, immunodominant epitopes in the HA2 subunit remain largely unknown. To delineate MHC Class I epitopes, we first identified 9-mer H-2Kd -restricted CD8 T cell epitopes in the HA2 domain by in silico analyses, followed by evaluating the immunodominance of these peptides in mice challenged with the virus...
May 21, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29789639/fludarabine-and-neurotoxicity-in-engineered-t-cell-therapy
#2
Kate L Lowe, Crystal L Mackall, Elliot Norry, Rafael Amado, Bent K Jakobsen, Gwendolyn Binder
Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension...
May 7, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29777029/cd4-t-cell-affinity-diversity-is-equally-maintained-during-acute-and-chronic-infection
#3
Rakieb Andargachew, Ryan J Martinez, Elizabeth M Kolawole, Brian D Evavold
TCR affinity for peptide MHC dictates the functional efficiency of T cells and their propensity to differentiate into effectors and form memory. However, in the context of chronic infections, it is unclear what the overall profile of TCR affinity for Ag is and if it differs from acute infections. Using the comprehensive affinity analysis provided by the two-dimensional micropipette adhesion frequency assay and the common indirect affinity evaluation methods of MHC class II tetramer and functional avidity, we tracked IAb GP61-80 -specific cells in the mouse model of acute (Armstrong) and chronic (clone 13) lymphocytic choriomeningitis virus infection...
May 18, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29774664/the-lupus-associated-fc%C3%AE-riib-i232t-polymorphism-results-in-impairment-in-the-negative-selection-of-low-affinity-germinal-center-b-cells-via-c-abl
#4
Jyun-Pei Jhou, I-Shing Yu, Haw Hwai, Chih-Shan Chen, Pei-Lung Chen, Shiang-Jong Tzeng
OBJECTIVE: FcγRIIB is an essential negative regulator of B cells to block BCR signaling and to trigger c-Abl-dependent apoptosis of B cells. FcγRIIB-deficient mice display splenomegaly with expansion of B cells, leading to lupus. FcγRIIB-I232T is a hypo-functional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of FcγRIIB-I232T polymorphism, we investigated the role of FcγRIIB in the deletion of low-affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity...
May 17, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29774024/quantification-of-hla-dm-dependent-major-histocompatibility-complex-of-class-ii-immunopeptidomes-by-the-peptide-landscape-antigenic-epitope-alignment-utility
#5
Miguel Álvaro-Benito, Eliot Morrison, Esam T Abualrous, Benno Kuropka, Christian Freund
The major histocompatibility complex of class II (MHCII) immunopeptidome represents the repertoire of antigenic peptides with the potential to activate CD4+ T cells. An understanding of how the relative abundance of specific antigenic epitopes affects the outcome of T cell responses is an important aspect of adaptive immunity and offers a venue to more rationally tailor T cell activation in the context of disease. Recent advances in mass spectrometric instrumentation, computational power, labeling strategies, and software analysis have enabled an increasing number of stratified studies on HLA ligandomes, in the context of both basic and translational research...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29772075/cd6-mabs-differ-in-epitope-kinetics-and-mechanism-of-action
#6
Lee I Garner, Andrew Hartland, Johannes Breuning, Marion H Brown
CD6 is a type I T cell surface receptor which modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab™ ) which has reached the clinic for treatment of autoimmune disease. We characterised molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action...
May 17, 2018: Immunology
https://www.readbyqxmd.com/read/29769329/isolation-of-state-dependent-monoclonal-antibodies-against-the-12-transmembrane-domain-glucose-transporter-4-using-virus-like-particles
#7
David F Tucker, Jonathan T Sullivan, Kimberly-Anne Mattia, Christine R Fisher, Trevor Barnes, Manu N Mabila, Rona Wilf, Chidananda Sulli, Meghan Pitts, Riley J Payne, Moniquetta Hall, Duncan Huston-Paterson, Xiaoxiang Deng, Edgar Davidson, Sharon H Willis, Benjamin J Doranz, Ross Chambers, Joseph B Rucker
The insulin-responsive 12-transmembrane transporter GLUT4 changes conformation between an inward-open state and an outward-open state to actively facilitate cellular glucose uptake. Because of the difficulties of generating conformational mAbs against complex and highly conserved membrane proteins, no reliable tools exist to measure GLUT4 at the cell surface, follow its trafficking, or detect the conformational state of the protein. Here we report the isolation and characterization of conformational mAbs that recognize the extracellular and intracellular domains of GLUT4, including mAbs that are specific for the inward-open and outward-open states of GLUT4...
May 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29769195/osteocyte-driven-downregulation-of-snail-restrains-effects-of-drd2-inhibitors-on-mammary-tumor-cells
#8
Shengzhi Liu, Yao Fan, Andy Chen, Aydin Jalali, Kazumasa Minami, Kazuhiko Ogawa, Harikrishna Nakshatri, Bai-Yan Li, Hiroki Yokota
While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, Fluphenazine (FP) and Trifluoperazine (TFP), on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1)...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29763554/template-catalyzed-disulfide-conjugation-of-monoclonal-antibodies-using-a-natural-amino-acid-tag
#9
Jeremy D King, Yuelong Ma, Yi-Chui Kuo, Krzysztof P Bzymek, Leah H Goodstein, Kassondra Meyer, Roger E Moore, Desiree Crow, David Colcher, Gagandeep Singh, David A Horne, John C Williams
The high specificity and favorable pharmacological properties of monoclonal antibodies (mAbs) have prompted significant interest in re-engineering this class of molecules to add novel functionalities for enhanced therapeutic and diagnostic potential. Here, we used the high affinity, meditope-Fab interaction to template and drive the rapid, efficient, and stable site-specific formation of a disulfide bond. We demonstrate that this template-catalyzed strategy provides a consistent and reproducible means to conjugate fluorescent dyes, cytotoxins, or "click" chemistry handles to meditope-enabled mAbs (memAbs) and memFabs...
May 15, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29760216/-plasmodium-falciparum-msp3-exists-in-a-complex-on-the-merozoite-surface-and-generates-antibody-response-during-natural-infection
#10
Arunaditya Deshmukh, Bishwanath Kumar Chourasia, Sonali Mehrotra, Ikhlaq Hussain Kana, Gourab Paul, Ashutosh Panda, Inderjeet Kaur, Susheel Kumar Singh, Sumit Rathore, Aparup Das, Priya Gupta, Kalamuddin Md, S K Ghakar, Asif Mohmmed, Michael Theisen, Pawan Malhotra
Plasmodium falciparum merozoite surface protein 3 (MSP3) is an abundantly expressed secreted merozoite surface protein and a leading malaria vaccine candidate antigen. However, it is unclear how MSP3 is retained on the surface of merozoites without a GPI anchor or a transmembrane domain. In the present study, we identified an MSP3 associated network on the Plasmodium merozoite surface by Immunoprecipitation of Plasmodium merozoite lysate using anti-MSP3N antibodies followed by mass spectrometry analysis. The results suggested the association of MSP3 with other merozoite surface proteins; MSP1, MSP6, MSP7, RAP2 and SERA5...
May 14, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29758051/the-effect-of-acylation-with-fatty-acids-and-other-modifications-on-hla-class-ii-peptide-binding-and-t-cell-stimulation-for-three-model-peptides
#11
Heidi S Schultz, Søren Østergaard, John Sidney, Kasper Lamberth, Alessandro Sette
Immunogenicity is a major concern in drug development as anti-drug antibodies in many cases affect both patient safety and drug efficacy. Another concern is often the limited half-life of drugs, which can be altered by different chemical modifications, like acylation with fatty acids. However, acylation with fatty acids has been shown in some cases to modulate T cell activation. Therefore, to understand the role of acylation with fatty acids on immunogenicity we tested three immunogenic non-acylated peptides and 14 of their acylated analogues for binding to 26 common HLA class II alleles, and their ability to activate T cells in an ex vivo T cell assay...
2018: PloS One
https://www.readbyqxmd.com/read/29757907/t-follicular-regulatory-cells-and-antibody-responses-in-transplantation
#12
E F Wallin
De novo donor specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitisation, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Tfr cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses...
May 1, 2018: Transplantation
https://www.readbyqxmd.com/read/29750515/dimerization-through-the-ring-finger-domain-attenuates-excision-activity-of-the-piggybac-transposase
#13
Rahul Sharma, Shivlee Nirwal, Naveen Narayanan, Deepak T Nair
The movement of the piggyBac transposon is mediated through its cognate transposase. The piggyBac transposase binds to the terminal repeats present at the ends of the transposon. This is followed by excision of the transposon and release of the nucleoprotein complex. The complex translocates, followed by integration of the transposon at the target site. Here, we show that the RING-finger domain (RFD) present toward the C-terminus of the transposase is vital for dimerization of this enzyme. The deletion of the RFD or the last seven residues of the RFD results in a monomeric protein that binds the terminal end of the transposon with nearly the same affinity as wild type piggyBac transposase...
May 11, 2018: Biochemistry
https://www.readbyqxmd.com/read/29748061/massive-ggaas-in-genomic-repetitive-sequences-serve-as-a-nuclear-reservoir-of-nf-%C3%AE%C2%BAb
#14
Jian Wu, Qiao Wang, Wei Dai, Wei Wang, Ming Yue, Jinke Wang
Nuclear factor κB (NF-κB) is a DNA-binding transcription factor. Characterizing its genomic binding sites is crucial for understanding its gene regulatory function and mechanism in cells. This study characterized the binding sites of NF-κB RelA/p65 in the tumor neurosis factor-α (TNFα) stimulated HeLa cells by a precise chromatin immunoprecipitation-sequencing (ChIP-seq). The results revealed that NF-κB binds nontraditional motifs (nt-motifs) containing conserved GGAA quadruplet. Moreover, nt-motifs mainly distribute in the peaks nearby centromeres that contain a larger number of repetitive elements such as satellite, simple repeats and short interspersed nuclear elements (SINEs)...
April 13, 2018: Journal of Genetics and Genomics, Yi Chuan Xue Bao
https://www.readbyqxmd.com/read/29747819/protein-toxins-that-utilize-gangliosides-as-host-receptors
#15
Madison Zuverink, Joseph T Barbieri
Subsets of protein toxins utilize gangliosides as host receptors. Gangliosides are preferred receptors due to their extracellular localization on the eukaryotic cell and due to their essential nature in host physiology. Glycosphingolipids, including gangliosides, are mediators of signal transduction within and between eukaryotic cells. Protein toxins possess AB structure-function organization, where the A domain encodes a catalytic function for the posttranslational modification of a host macromolecule, including proteins and nucleic acids, and a B domain, which encodes host receptor recognition, including proteins and glycosphingolipids, alone or in combination...
2018: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29747818/glycan-chains-of-gangliosides-functional-ligands-for-tissue-lectins-siglecs-galectins
#16
Robert W Ledeen, Jürgen Kopitz, José Abad-Rodríguez, Hans-Joachim Gabius
Molecular signals on the cell surface are responsible for adhesion and communication. Of relevance in this respect, their chemical properties endow carbohydrates with the capacity to store a maximum of information in a minimum of space. One way to present glycans on the cell surface is their covalent conjugation to a ceramide anchor. Among the resulting glycosphingolipids, gangliosides are special due to the presence of at least one sialic acid in the glycan chains. Their spatial accessibility and the dynamic regulation of their profile are factors that argue in favor of a role of glycans of gangliosides as ligands (counterreceptors) for carbohydrate-binding proteins (lectins)...
2018: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29743315/an-unmutated-igm-response-to-the-vi-polysaccharide-of-salmonella-typhi-contributes-to-protective-immunity-in-a-murine-model-of-typhoid
#17
Kalgi D Pandya, Isabel Palomo-Caturla, Justin A Walker, Vijay K Sandilya, Zhijiu Zhong, Kishore R Alugupalli
T cell-dependent B cell responses typically develop in germinal centers. Abs generated during such responses are isotype switched and have a high affinity to the Ag because of somatic hypermutation of Ab genes. B cell responses to purified polysaccharides are T cell independent and do not result in the formation of bona fide germinal centers, and the dominant Ab isotype produced during such responses is IgM with very few or no somatic mutations. Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and Ig isotype switching in humans and mice...
May 9, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29743176/warfarin-and-vitamin-k-epoxide-reductase-a-molecular-accounting-for-observed-inhibition
#18
Sangwook Wu, Xuejie Chen, Da-Yun Jin, Darrel W Stafford, Lee G Pedersen, Jian-Ke Tie
Vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K-dependent carboxylation, a post-translational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant warfarin. However, the topological structure of VKOR and the mechanism of warfarin's inhibition of VKOR remain elusive. Additionally, it is not clear why warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin's binding affinity, but have only a minor effect on vitamin K binding...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29742893/synthesis-liposomal-formulation-and-immunological-evaluation-of-a-minimalistic-carbohydrate-%C3%AE-galcer-vaccine-candidate
#19
Felix Broecker, Sebastian Götze, Jonathan Hudon, Dominea C K Rathwell, Claney L Pereira, Pierre Stallforth, Anish Chakkumkal, Peter H Seeberger
Fully synthetic glycan-based vaccines hold great potential as preventive and therapeutic vaccines against infectious diseases as well as cancer. Here, we present a two-component platform based on the facile conjugation of carbohydrate antigens to α-galactosylceramide (α-GalCer) to yield fully synthetic vaccine candidates. Formulation of a cancer-associated Tn antigen glycolipid model vaccine candidate into liposomes of different sizes and subsequent immunization of mice generated specific, high-affinity antibodies against the carbohydrate antigen with characteristics of T cell-dependent immunity...
May 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29741477/empty-conformers-of-hla-b-preferentially-bind-cd8-and-regulate-cd8-t-cell-function
#20
Jie Geng, John D Altman, Sujatha Krishnakumar, Malini Raghavan
When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode...
May 9, 2018: ELife
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