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Antigen binding recepters

Jiansheng Jiang, Kannan Natarajan, Lisa F Boyd, Giora I Morozov, Michael G Mage, David H Margulies
Central to CD8+ T cell-mediated immunity is the recognition of peptide-major histocompatibility complex class I (p-MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein-related), a tapasin homolog...
November 24, 2017: Science
Andy van Hateren, Malcolm Anderson, Alistair Bailey, Jörn M Werner, Paul Skipp, Tim Elliott
Major histocompatibility complex class I molecules (MHC I) help protect jawed vertebrates by binding and presenting immunogenic peptides to cytotoxic T lymphocytes. Peptides are selected from a large diversity present in the endoplasmic reticulum. However, only a limited number of peptides complement the polymorphic MHC specificity determining pockets in a way that leads to high-affinity peptide binding and efficient antigen presentation. MHC I molecules possess an intrinsic ability to discriminate between peptides, which varies in efficiency between allotypes, but the mechanism of selection is unknown...
December 8, 2017: Journal of Biological Chemistry
Filip Kveton, Anna Blšáková, Andras Hushegyi, Pavel Damborsky, Ola Blixt, Bo Jansson, Jan Tkac
The main aim of the study was to optimize the interfacial presentation of a small antigen-a Tn antigen (N-acetylgalactosamine)-for binding to its analyte anti-Tn antibody. Three different methods for the interfacial display of a small glycan are compared here, including two methods based on the immobilization of the Tn antigen on a mixed self-assembled monolayer (SAM) (2D biosensor) and the third one utilizing a layer of a human serum albumin (HSA) for the immobilization of a glycan forming a 3D interface. Results showed that the 3D interface with the immobilized Tn antigen is the most effective bioreceptive surface for binding its analyte...
March 21, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Shen-An Hwang, Marian L Kruzel, Jeffrey K Actor
Lactoferrin, an iron-binding glycoprotein found in mammalian mucosal secretions and granules of neutrophils, possesses several immune modulatory properties. Published reports indicate that lactoferrin enhances the efficacy of the tuberculosis vaccine, BCG (Bacillus Calmette Guerin), both by increasing macrophage and dendritic cell ability to stimulate receptive T cells and by modulating the inflammatory response. This report is the first to demonstrate the effects of a recombinant human lactoferrin (10 μg/mL) on human PBMC derived CD14+ and CD16+ macrophages stimulated with a strong (LPS, 10 ng/mL) or weaker (BCG, MOI 1:1) stimulator of inflammation...
December 2016: Tuberculosis
Giora I Morozov, Huaying Zhao, Michael G Mage, Lisa F Boyd, Jiansheng Jiang, Michael A Dolan, Ramesh Venna, Michael A Norcross, Curtis P McMurtrey, William Hildebrand, Peter Schuck, Kannan Natarajan, David H Margulies
Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8(+) T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I...
February 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
Olivier Fisette, Sebastian Wingbermühle, Robert Tampé, Lars V Schäfer
Immune recognition of infected or malignantly transformed cells relies on antigenic peptides exposed at the cell surface by major histocompatibility complex class I (MHC I) molecules. Selection and loading of peptides onto MHC I is orchestrated by the peptide-loading complex (PLC), a multiprotein assembly whose structure has not yet been resolved. Tapasin, a central component of the PLC, stabilises MHC I and catalyses the exchange of low-affinity against high-affinity, immunodominant peptides. Up to now, the molecular basis of this peptide editing mechanism remained elusive...
January 12, 2016: Scientific Reports
Clemens Hermann, Andy van Hateren, Nico Trautwein, Andreas Neerincx, Patrick J Duriez, Stefan Stevanović, John Trowsdale, Janet E Deane, Tim Elliott, Louise H Boyle
Our understanding of the antigen presentation pathway has recently been enhanced with the identification that the tapasin-related protein TAPBPR is a second major histocompatibility complex (MHC) class I-specific chaperone. We sought to determine whether, like tapasin, TAPBPR can also influence MHC class I peptide selection by functioning as a peptide exchange catalyst. We show that TAPBPR can catalyse the dissociation of peptides from peptide-MHC I complexes, enhance the loading of peptide-receptive MHC I molecules, and discriminate between peptides based on affinity in vitro...
October 6, 2015: ELife
Liusong Yin, Zachary J Maben, Aniuska Becerra, Lawrence J Stern
Ag presentation by MHC class II (MHC II) molecules to CD4(+) T cells plays a key role in the regulation of the adaptive immune response. Loading of antigenic peptides onto MHC II is catalyzed by HLA-DM (DM), a nonclassical MHC II molecule. The mechanism of DM-facilitated peptide loading is an outstanding problem in the field of Ag presentation. In this study, we systemically explored possible kinetic mechanisms for DM-catalyzed peptide association by measuring real-time peptide association kinetics using fluorescence polarization assays and comparing the experimental data with numerically modeled peptide association reactions...
July 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Soumya Badrinath, Heike Kunze-Schumacher, Rainer Blasczyk, Trevor Huyton, Christina Bade-Doeding
While many HLA class I molecules interact directly with the peptide loading complex (PLC) for conventional loading of peptides certain class I molecules are able to present peptides in a way that circumvents the PLC components. We investigated micropolymorphisms at position 156 of HLA-A(*)24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA-A(*)24:06(156Trp) and HLA-A(*)24:13(156Leu) showed high levels of cell surface expression while HLA-A(*)24:02(156Gln) was expressed at low levels in tapasin deficient cells...
2014: Journal of Immunology Research
Sebastián Montealegre, Vaishnavi Venugopalan, Susanne Fritzsche, Corinna Kulicke, Zeynep Hein, Sebastian Springer
Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2K(b) class I proteins from the cell surface...
July 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Saifullah Afridi, Farzana Shaheen, Olaf Roetzschke, Zafar Ali Shah, Syed Comail Abbas, Rizwana Siraj, Talat Makhmoor
Major histocompatibility complex (MHC)-loading enhancers (MLE) have recently attracted attention because of their ability to enhance the efficacy of peptide immunotherapeutics. As small molecular weight compounds, they influence the loading of peptides in MHC molecules by converting them from a non-receptive to a receptive state. Herein, we report a 14-mer cyclic peptide 1 (CP-1) as a new class of MLE-peptide. This peptide was used to investigate its loading on human leukocyte antigen (HLA)-DR molecules. It was found that CP-1 strongly accelerates peptide-loading on both soluble and cell surface HLA-DR molecules in a dose-dependent manner...
January 16, 2015: Biochemical and Biophysical Research Communications
Connie E Poon, Romanthi J Madawala, Margot L Day, Christopher R Murphy
The non-receptive uterine luminal epithelium forms a polarised epithelial barrier, protective against potential pathogenic assault from the external environment and invasion by the blastocyst. However, during the window of implantation, the uterine luminal epithelial cells (UECs) transition to a receptive state by dismantling many of their intercellular and cell-matrix adhesions in preparation for epithelial detachment and subsequent blastocyst implantation. The present study investigated the presence and regulation of the intercellular adhesion protein, Epithelial Cell Adhesion Molecule (EpCAM) during early pregnancy in the rat to understand its role in the transition to receptivity...
February 2015: Cell and Tissue Research
M Schmitt, M Metzger, D Gradl, G Davidson, V Orian-Rousseau
Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration-dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization...
April 2015: Cell Death and Differentiation
Hirofumi Haraguchi, Tomoko Saito-Fujita, Yasushi Hirota, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Naoko Yamauchi, Masashi Fukayama, Amanda Bartos, Jeeyeon Cha, Sudhansu K Dey, Tomoyuki Fujii, Yutaka Osuga
Although cervical pregnancy and placenta previa, in which the embryo and placenta embed in or adjacent to the cervix, are life-threatening complications that result in massive bleeding and poor pregnancy outcomes in women, the incidence of these aberrant conditions is uncommon. We hypothesized that a local molecular mechanism is normally in place to prevent embryo implantation in the cervix. The ovarian hormones progesterone (P(4)) and estrogen differentially direct differentiation and proliferation of endometrial cells, which confers the receptive state for implantation: P(4) dominance causes differentiation of the luminal epithelium but increases stromal cell proliferation in preparation of the uterus for implantation...
July 2014: Molecular Endocrinology
Deepak K Nayak, Boris Calderon, Anthony N Vomund, Emil R Unanue
Autoantibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified in patients with type 1 diabetes. Here we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse. Immunization with a cytoplasmic domain of the protein or with peptides predicted to bind to I-A(g7) resulted in a CD4 T-cell response, indicating a lack of deletional tolerance. However, presentation by intraislet antigen-presenting cells (APC) to the T cells was not detectable in prediabetic mice...
October 2014: Diabetes
Flávio C B Fernandes, Adriano Santos, Denise C Martins, Márcio S Góes, Paulo R Bueno
The transducer faradaic signals of molecularly receptive interfaces associated with specific target binding can be sensitively monitored by electrochemical impedance and/or capacitance spectroscopies. A comparative evaluation of both impedimetric (associated with charge transfer resistance) and capacitive (associated with faradaic density of states) approaches was undertaken using C-reactive protein (CRP) antigen and antibody interaction as biomolecular binding model. Aiming at constructing redox free (impedimetric) and redox tethered receptive (capacitive) interfaces engineered by self-assembly monolayer, CRP sensitivity and limit of detections were comparatively assessed regarding biosensor capabilities...
July 15, 2014: Biosensors & Bioelectronics
Miklós Sárvári, Imre Kalló, Erik Hrabovszky, Norbert Solymosi, Zsolt Liposits
The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER) agonists...
2014: PloS One
Sunil Kumar Saini, Katja Ostermeir, Venkat Raman Ramnarayan, Heiko Schuster, Martin Zacharias, Sebastian Springer
MHC class I molecules bind only those peptides with high affinity that conform to stringent length and sequence requirements. We have now investigated which peptides can aid the in vitro folding of class I molecules, and we find that the dipeptide glycyl-leucine efficiently supports the folding of HLA-A*02:01 and H-2K(b) into a peptide-receptive conformation that rapidly binds high-affinity peptides. Treatment of cells with glycyl-leucine induces accumulation of peptide-receptive H-2K(b) and HLA-A*02:01 at the surface of cells...
September 17, 2013: Proceedings of the National Academy of Sciences of the United States of America
Monika-Sarah E D Schulze, Anne-Kathrin Anders, Dhruv K Sethi, Melissa J Call
Peptide presentation by MHC class II is of critical importance to the function of CD4+ T cells. HLA-DM resides in the endosomal pathway and edits the peptide repertoire of newly synthesized MHC class II molecules before they are exported to the cell surface. HLA-DM ensures MHC class II molecules bind high affinity peptides by targeting unstable MHC class II:peptide complexes for peptide exchange. Research over the past decade has implicated the peptide N-terminus in modulating the ability of HLA-DM to target a given MHC class II:peptide combination...
2013: PloS One
Yuri O Poluektov, Aeryon Kim, Isamu Z Hartman, Scheherazade Sadegh-Nasseri
Processing of antigens for presentation to helper T cells by MHC class II involves HLA-DM (DM) and HLA-DO (DO) accessory molecules. A mechanistic understanding of DO in this process has been missing. The leading model on its function proposes that DO inhibits the effects of DM. To directly study DO functions, we designed a recombinant soluble DO and expressed it in insect cells. The kinetics of binding and dissociation of several peptides to HLA-DR1 (DR1) molecules in the presence of DM and DO were measured...
2013: PloS One
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