MICA shedding is thought to be the principal mechanism by which tumor cells escape from NKG2D- mediated immunosurveillance.13 In this study, we demonstrated that ADAM9 was overexpressed in human HCC tissues and that ADAM9 knockdown resulted in increased expression of membrane-bound MICA, decreased production of soluble MICA, and up-regulation of NK sensitivity of human HCC cells. These results point to ADAM9 as a possible therapeutic target for inhibiting MICA shedding, thereby increasing immunity against HCC.. We identified the ADAM9 cleavage site of MICA in vitro, which is located at the intracellular domain of MICA. ADAM9 protease is usually located in the extracellular area, but we revealed that ADAM9 protease is required for the production of not only the 37 kD soluble MICA but also the 39 kD MICA in HCC cells. Based on our present data, it is speculated that ADAM9 protease may enable intracellular cleavage of MICA protein by activating some intracellular protease which can recognize a ...
TY - JOUR. T1 - Interferons up-regulate with different potency HLA class I antigen expression in M14 human melanoma cell line. Possible interaction with glucocorticoid hormones. AU - Lanza, Lorella. AU - Peirano, Lorenza. AU - Bosco, Ornella. AU - Contini, Paola. AU - Filaci, Gilberto. AU - Setti, Maurizio. AU - Puppo, Francesco. AU - Indiveri, Francesco. AU - Scudeletti, Marco. PY - 1995/1. Y1 - 1995/1. N2 - The relative potency of interferon α (IFNα), interferon β (IFNβ), and interferon γ (IFNγ) in inducing the expression of HLA class I antigens, as well as their capacity to counteract the inhibition induced by glucocorticoid hormones on HLA class I antigen expression, were analysed in the human melanoma cell line M14, both at membrane and at mRNA level. The data obtained indicate that (a) IFN enhance with different potency (IFNγ,IFNβ,IFNα) the expression of HLA class I antigens in M14 cells, (b) prednisone inhibits HLA class I antigen expresion, (c) glucocorticoid hormones, when ...
TY - JOUR. T1 - Expression of the major histocompatibility complex class I molecule Mamu-A*01 is associated with control of simian immunodeficiency virus SIVmac239 replication. AU - Mothé, Bianca R.. AU - Weinfurter, Jason. AU - Wang, Chenxi. AU - Rehrauer, William. AU - Wilson, Nancy. AU - Allen, Todd M.. AU - Allison, David B.. AU - Watkins, David. PY - 2003/2/1. Y1 - 2003/2/1. N2 - Several HLA alleles are associated with attenuated human immunodeficiency virus disease progression. We explored the relationship between the expression of particular major histocompatibility complex (MHC) class I alleles and viremia in simian immunodeficiency virus SIVmac239-infected macaques. Of the common MHC class I alleles, animals that expressed Mamu-A*01 exhibited the best control of viral replication.. AB - Several HLA alleles are associated with attenuated human immunodeficiency virus disease progression. We explored the relationship between the expression of particular major histocompatibility complex ...
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BY55 is a human cell surface molecule whose expression is restricted to NK cells, a subset of circulating CD8+ T lymphocytes, and all intestinal intraepithelial T lymphocytes. Here, we report that BY55 is a novel NK receptor showing broad specificity for both classical and nonclassical MHC class I molecules, and that optimal binding requires a prior aggregation of MHC class I complexes. Using BY55 transfectants, we have identified functional consequences of MHC class I/ligand interactions for the class I-bearing cell. The triggering of MHC class I molecules on human T cell clones by BY55 delivered a potent proliferative signal in the presence of soluble CD3 mAb. The costimulatory signal provided by MHC class I ligation was only seen in activated, and not resting, peripheral blood T cells. This observation represents an additional and/or alternative pathway to CD28 costimulation and may be of particular relevance in memory T cells lacking CD28, such as intestinal intraepithelial T lymphocytes, which are
The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the cytosol. TAP binds peptides on the cytoplasmic side and translocates them under ATP consumption into the lumen of the ER. The MHC class I molecule is then, in turn, loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex called the Peptide loading complex[7] consisting of TAP, tapasin, calreticulin, calnexin, and Erp57 (PDIA3). Calnexin acts to stabilize the class I MHC α chains prior to β2m binding. Following complete assembly of the MHC molecule, calnexin dissociates. The MHC molecule lacking a bound peptide is inherently unstable and requires the ...
A large number of natural killer (NK) cells with high function are expected to generate especially in tumor adoptive immunotherapy. Here K562 cells were genetically modified to co-express major histocompatibility complex class I chain-related protein A (MICA), 4-1BB ligand, and IL-15, called K562-MICA-4-1BBL-IL-15. The modified K562 cells not only promoted activation, proliferation, and survival of NK cells, but also enhanced NK cell cytotoxicity. In long-term culture tests, K562-MICA-4-1BBL-IL-15 cells stimulated NK cell to expand mean 550 folds in 24-day culture and to cover from 14.8% of total peripheral blood monoclonal lymphocytes on day 1 to 86.7% on day 24. Prevalent NK cells after expansion enhanced the ability of killing targets and producing interferon gamma (IFN-γ), and kept high expression of activating receptors. The results indicated that K562-MICA-4-1BBL-IL-15 cells would be developed for expansion of NK cells ex vivo and may have important implications for clinical immunotherapy.
Mhc class I molecules display intracellularly derived peptides on the surface of almost all nucleated mammalian cells for recognition by the immune system. MHC class I heavy chain, which contains the peptide binding site, is a classical type I transmembrane protein with a large luminal/extracellular domain and a short cytosolic tail. The heavy chain enters the secretory pathway via the ER translocon, a channel whose major component is Sec61. The light chain β2 microglobulin (β2m)1 and the peptide associate with the heavy chain after it has been inserted into the ER membrane, and the complex is then transported, via the Golgi, to the plasma membrane. In humans, the MHC class I heavy chain is a 43-kD protein that contains a single N-linked glycan.. Human cytomegalovirus (HCMV) evades detection by the immune system by targeting MHC class I heavy chains for destruction soon after they have been synthesized. The HCMV proteins responsible for MHC class I heavy chain destruction are US11 and US2 ...
Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLAgenes, and beta-2-microglobulin (β2M) are membrane proteins on all...
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TY - JOUR. T1 - Bacterial and Host Factors Involved in the Major Histocompatibility Complex Class Ib-Restricted Presentation of Salmonella Hsp 60. T2 - Novel Pathway. AU - Lo, Wei Feng. AU - Dunn, Cory D.. AU - Ong, Helena. AU - Metcalf, Eleanor S.. AU - Soloski, Mark J.. PY - 2004/5/1. Y1 - 2004/5/1. N2 - Previously, a peptide epitope derived from the Hsp 60 molecule of Salmonella that is presented by the major histocompatibility complex (MHC) class Ib molecule Qa-1 to CD8+ cytotoxic T cells (CTLs) was described. In the present study we investigated the Salmonella-induced processing and presentation pathway for generating this Qa-1-restricted epitope. Live bacteria and, to a lesser extent, opsonized heat-killed bacteria are able to sensitize target cells for lysis by Salmonella-specific CTL. In contrast, heat-killed bacteria cannot sensitize target cells. Presentation of the Hsp 60 epitope appears independent of bacterial internalization, because cytochalasin D does not affect presentation. ...
Chimpanzees have got orthologs of the six, fixed, functional human genes. cytoplasmic tails. Systematic mutagenesis showed that each substitution contributes changes in cell-surface expression. The combination of residues present in Patr-AL appears unique, but each individual residue is present in other primate MHC class I molecules, notably MHC-E, the most ancient of Gusb the functional human MHC class I molecules. INTRODUCTION The selective pressures imposed by diverse, fast-evolving pathogens cause the MHC class I genes of their mammalian hosts also to evolve rapidly (1). As a consequence there is considerable species-specific character to gene families. Characteristics shared by most mammalian species are highly polymorphic classical MHC class I molecules that engage highly variable types of lymphocyte receptor and conserved non-classical MHC class I molecules that engage conserved types of lymphocyte receptors. Of the six human genes that are functional, and are highly polymorphic and ...
article{f66fe82b-15d5-4f5b-963e-718069cb47dc, abstract = {,p,The assembly of MHC class I molecules is regulated by a multi-protein complex in the endoplasmic reticules (ER) termed the loading complex. Tapasin is suggested to be one of the molecules forming this complex on the basis of its interaction with both the transporter associated with antigen processing (TAP) and MHC class I molecules. To address whether TAP is indispensable for the processing of the assembly of tapasin-associated MHC class I molecules, we studied the association of MHC class I molecules with tapasin, the assembly of tapasin-associated MHC class I with peptides and the peptide-mediated dissociation of MHC class I from tapasin in TAP-mutant T2 cells. In the absence of TAP, MHC class I heavy chain and beta(2)-microglobulin dimers were found to be properly associated with tapasin. The stable MHC class I dimer was required for its association with tapasin in the ER. In the absence of TAP, tapasin retained MHC class I ...
The Allele Frequency Net Database (AFND) is a public database which contains frequency information of several immune genes such as Human Leukocyte Antigens (HLA), Killer-cell Immunoglobulin-like Receptors (KIR), Major histocompatibility complex class I chain-related (MIC) genes, and a number of cytokine gene polymorphisms. The Allele Frequency Net Database (AFND) provides a central source, freely available to all, for the storage of allele frequencies from different polymorphic areas in the Human Genome. Users can contribute the results of their work into one common database and can perform database searches on information already available. We have currently collected data in allele, haplotype and genotype format. However, the success of this website will depend on you to contribute your data ...
Tcells recognize Ags complexed to MHC molecules. In general, MHC class I molecules are complexed with peptides (CD8 T cell epitopes) derived from cytosolic Ag, and MHC class II molecules are complexed with peptides from internalized Ag (CD4 T cell epitopes) (1, 2). However, when APC such as dendritic cells (DCs)3 internalize high amounts of Ag, they appear to be able to route internalized Ag into the MHC class I presentation pathway, a process termed cross-presentation (3). Cross-presentation of Ag via MHC class I molecules can lead to activation/priming of naive CD8 T cells, a process referred to as cross-priming (4), to paralysis/deletion, or to cross-tolerance (5).. Immature DCs lack costimulatory signals required for productive T cell activation but are well equipped to sample Ag, for example via receptor-mediated endocytosis or fluid phase pinocytosis (6). Because of its selectivity for the Ag in question, the efficacy of Ag internalization via receptor-mediated endocytosis is high, ...
We applied doses between 1-25 Gy, which is lower or comparable with doses received by patients, and observed that ionizing radiation induces a dose-dependent increase in MHC class I presentation in two phases (Fig. 6). The first phase represents peptides derived from existing proteins, because inhibition of translation does not affect the generation of these peptides. More polyubiquitinated proteins for proteasomal degradation are observed swiftly after radiation even at doses of 1-4 Gy, resulting in more peptides for MHC class I antigen presentation and enhanced MHC class I expression as peptides are the limiting step in complex formation (37). Irradiation will result in the formation of free radicals even at low doses, and proteins will be modified directly by radiation or indirectly by radicals formed after water radiolysis, resulting in oxidation of various amino acids. These modifications may target the affected proteins for rapid degradation by the proteasome. Although this will reflect a ...
Human cytomegalovirus encodes two glycoproteins, US2 and US11, which cause rapid degradation of MHC class I molecules, thus preventing recognition of virus-infected cells by the immune system. This degradation process involves retrograde transport or dislocation of MHC class I molecules from the endoplasmic reticulum (ER) to the cytosol, where they are deglycosylated by an N-glycanase and degraded by the proteasome. At present it is unknown whether ubiquitination is required for US2- and US11-mediated dislocation and degradation of MHC class I molecules. Here, we show that in E36ts20 hamster cells, which contain a temperature-sensitive mutation in the E1 ubiquitin-activating enzyme, US11-mediated degradation of MHC class I molecules is strongly impaired at the non-permissive temperature, indicating the necessity for ubiquitination in this process. We next addressed the question of whether ubiquitination is a condition for the retrograde movement of MHC class I molecules from the ER to the ...
As a member of the wwPDB, the RCSB PDB curates and annotates PDB data according to agreed upon standards. The RCSB PDB also provides a variety of tools and resources. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists.
TY - JOUR. T1 - Location of the epitope for an anti-CD8α antibody 53.6.7 which enhances CD8α-MHC class I interaction indicates antibody stabilization of a higher affinity CD8 conformation. AU - Devine, Lesley. AU - Hodsdon, Michael E.. AU - Daniels, Mark A.. AU - Jameson, Stephen C. AU - Kavathas, Paula B.. PY - 2004/5/15. Y1 - 2004/5/15. N2 - MHC class I tetramers are widely used, usually in combination with an antibody to CD8, to detect antigen specific T cells. Some anti-CD8α antibodies block the interaction of murine MHC class I tetramers with CD8 T cells, while others such as 53.6.7, enhance. To understand the molecular basis for this effect, we mapped the epitope for the enhancing antibody 53.6.7 and three other blocking antibodies using a panel of murine CD8α (Lyt-2) mutants expressed on COS-7 transfectants. Mutations in residues that contact MHC class I affected binding of the blocking antibodies. In contrast, antibody 53.6.7 was affected by a mutation in the residue T81A located on ...
We have used an in vitro system to study the effects of major histocompatibility complex class I binding peptides on thymic development. Fetal thymus lobes from mice deficient in the class I light chain (beta 2 microglobulin or beta 2 M-/-) were cultured for 10 d in vitro, during which time T cell precursors develop into mature T cells. In these organ cultures, as in the adult or neonatal beta 2 M-/- thymus, CD8+ mature T cells did not develop, demonstrating that the mature T cells seen during early murine thymic development are the result of the positive selection process. To these cultures we added various class I binding peptides with or without a source of exogenous beta 2M. CD8+ T cells developed to various degrees only in the presence of beta 2M and peptides. Using peptide mixtures of differing complexity, we showed that the efficiency of this process is dependent more on peptide complexity than on peptide concentration. These data argue for a specific role for peptides in the process of ...
We have studied the role of major histocompatibility complex (MHC) molecules in the regulation of intercellular adhesion of human B cells. We found that molecules able to bind to MHC class II molecules, such as monoclonal antibodies or staphylococcal enterotoxins, induced rapid and sustained homotypic adhesion of Epstein-Barr virus (EBV)-transformed B cell lines as well as peripheral blood B lymphocytes. Moreover, anti-MHC class I monoclonal antibodies also stimulated intercellular adherence. Adhesion induced upon MHC engagement was faster and stronger than that triggered by phorbol esters. It needed active metabolism, but divalent cations were not required. Monoclonal antibodies directed against LFA-1 (CD11a/CD18) or its ligand ICAM-1 (CD54) did not inhibit MHC class II-induced homotypic adhesion of various EBV-transformed B cell lines, nor of a variant of the B cell line Raji expressing very low LFA-1 surface levels. Moreover, EBV-transformed B cells from a severe lymphocyte adhesion deficiency
The major obstacle to successful islet transplantation is the potent T cell-mediated immune response occurring soon after the procedure that leads to β-cell damage (16). The interaction between MHC class I molecules and CD8+ T cells plays a major role in both allo- and xenograft rejection (33,34). MHC class I molecules are found on every nucleated cell of the body and consist of two components: the α chain (the heavy chain) and B2M (the light chain). The α chain and B2M are both essential for the proper folding of the entire MHC complex (35). Studies have shown that there is no detectable expression of MHC class I molecules on the surface of the cell in the absence of B2M (36).. We hypothesized that downregulation of B2M in pancreatic islet cells would lead to reduced recognition by T cells and, as a result, benefit the transplantation outcome. Therefore, the goal of our study was to downregulate B2M expression in human pancreatic islets before transplantation in B2M (null) NOD/scid mice ...
In this study, we describe the creation of class I MHC-deficient pigs by simultaneously disrupting seven alleles of classical class I SLA genes. At the time of publication, the animals have been healthy and growing well for 7 mo. All cell types tested from these animals exhibit total loss of cell surface class I MHC proteins. Inactivation of a single gene, β2m, also prevents expression of class I MHC heterotrimers at the cell surface. This disruption was not attempted because mice lacking β2m lose the ability to regulate iron homeostasis (30-32). The high efficiency of the gRNA/Cas9 technology enabled the rapid production of animals deficient in class I MHC. The relative ease of this approach may enable the rapid production of many novel species lacking class I MHC gene activity.. Multigene families can be difficult to analyze because of functional redundancies. Simultaneous inactivation of all related genes minimizes these challenges by creating a null background that enables the study of one ...
In the course of constructing a recombinant vaccinia virus encoding the influenza A nucleoprotein (NP) gene preceded by the hemagglutinin leader sequence, we isolated a single base-pair deletion mutant which gave rise to L+NP(1-159) in which only the first 159 amino acids were in frame. Despite this, when we infected target cells, we found that the point mutant was able to sensitize them for lysis not only by cytotoxic T cells recognizing residues 50-58 (the in-frame portion), but also by CTL to epitopes which are downstream of the mutation (366-374 and 378-386). Furthermore, normal C57BL/6 mice can be primed with the frameshift NP to recognize the immunodominant Db-restricted epitope 366-374 (which is out of frame). Experiments in which the mutant gene product was processed in the endoplasmic reticulum of target cells suggested that the apparent suppression occurred during polypeptide extension.
In the course of constructing a recombinant vaccinia virus encoding the influenza A nucleoprotein (NP) gene preceded by the hemagglutinin leader sequence, we isolated a single base-pair deletion mutant which gave rise to L+NP(1-159) in which only the first 159 amino acids were in frame. Despite this, when we infected target cells, we found that the point mutant was able to sensitize them for lysis not only by cytotoxic T cells recognizing residues 50-58 (the in-frame portion), but also by CTL to epitopes which are downstream of the mutation (366-374 and 378-386). Furthermore, normal C57BL/6 mice can be primed with the frameshift NP to recognize the immunodominant Db-restricted epitope 366-374 (which is out of frame). Experiments in which the mutant gene product was processed in the endoplasmic reticulum of target cells suggested that the apparent suppression occurred during polypeptide extension.
Little is known about the structure of major histocompatibility complex (MHC) molecules outside of mammals. Only one class I molecule in the chicken MHC is highly expressed, leading to strong genetic associations with infectious pathogens. Here, we report two structures of the MHC class I molecule BF2*2101 from the B21 haplotype, which is known to confer resistance to Mareks disease caused by an oncogenic herpesvirus. The binding groove has an unusually large central cavity, which confers substantial conformational flexibility to the crucial residue Arg9, allowing remodeling of key peptide-binding sites. The coupled variation of anchor residues from the peptide, utilizing a charge-transfer system unprecedented in MHC molecules, allows peptides with conspicuously different sequences to be bound. This promiscuous binding extends our understanding of ways in which MHC class I molecules can present peptides to the immune system and might explain the resistance of the B21 haplotype to Mareks disease.
The role of exocytosis of major histocompatibility complex (MHC) class I molecules in the presentation of antigens to mouse cytotoxic T lymphocytes (CTLs) was examined by use of a recombinant vaccinia virus that expresses the E19 glycoprotein from adenovirus. E19 blocked the presentation of vaccinia and influenza virus proteins to CTLs in a MHC class I allele-specific manner identical to its inhibition of MHC class I transport from the endoplasmic reticulum. This finding indicates that (i) the relevant parameter for antigen presentation is the rate of MHC class I molecule exocytosis, not the level of class I cell surface expression, and (ii) association of class I molecules with antigen is likely to occur within the endoplasmic reticulum. ...
|strong|Mouse anti Sheep MHC Class I monoclonal antibody, clone VPM19|/strong| recognizes the ovine homologue of the human MHC Class I, a monomorphic determinant expressed on the heavy chain of sheep …
Author(s): Chen, Keling | Advisor(s): Shastri, Nilabh | Abstract: Cytotoxic T cells monitor MHC class I complexes on antigen presenting cells for the potential presence of any non-self peptides that could derive from viral infection or cancerous cells. Effective immune surveillance requires that MHC class I molecules display a peptide repertoire on the surface representing all cellular proteins. This ensures that foreign antigens from all sources are presented. How the peptide repertoire can be comprehensive despite the large differences in abundance and stability of individual proteins is not known. The pioneer round of translation is the first round of translation that occurs on newly spliced mRNA. It is associated with nonsense-mediated decay of mRNAs, allowing cells to detect and eliminate the aberrant mRNAs containing premature stop codons. We showed here that the peptide presentation by MHC I molecules was strongly influenced by the pioneer round of translation. Inhibition of the pioneer round of
Circumstantial evidence for transfer of MHC molecules between cells of the immune system was reported already 30 y ago (25, 26). More recent data have conclusively shown that effector T cells acquire both MHC class I and II molecules from APC (11, 12, 27). Also, B cells acquire membrane antigens from surrounding cells, a phenomenon which is followed by a very efficient presentation of these antigens to T cells (10). We show here for the first time that receptor-mediated ligand acquisition occurs also for NK cells, both in vitro and in vivo. Inhibitory Ly49 receptors on NK cells specifically acquired MHC class I molecules from surrounding cells, both when normal NK cells were transferred into a host expressing the ligand for the Ly49 molecule analyzed, and also in vitro when cells transfected with Ly49A were cocultured with cells transfected with H-2Dd. Ligand acquisition was a very rapid event, occurring within 30 min in both systems. The amount of acquired molecules remained high as long as the ...
Abcam provides specific protocols for Anti-HLA Class I antibody [W6/32] (ab22432) : Flow cytometry protocols, Immunoprecipitation protocols…
Human leukocyte antigen (HLA)-independent, T cell-mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR-Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population ...
Mouse monoclonal antibody raised against native MHC Class I. Native purified whole mouse spleen cells. (MAB1363) - Products - Abnova
Motivation: MHC:peptide binding plays a central role in activating the immune surveillance. Computational approaches to determine T-cell epitopes restricted to any given major histocompatibility complex (MHC) molecule are of special practical value in the development of for instance vaccines with broad population coverage against emerging pathogens. Methods have recently been published that are able to predict peptide binding to any human MHC class I molecule. In contrast to conventional allele-specific methods, these methods do allow for extrapolation to uncharacterized MHC molecules. These pan-specific human lymphocyte antigen (HLA) predictors have not previously been compared using independent evaluation sets.. Result: A diverse set of quantitative peptide binding affinity measurements was collected from Immune Epitope database (IEDB), together with a large set of HLA class I ligands from the SYFPEITHI database. Based on these datasets, three different pan-specific HLA web-accessible ...
Understanding the structure and variability of adaptive loci such as the major histocompatibility complex (MHC) genes is a primary research goal for evolutionary and conservation genetics. Typically, classical MHC genes show high polymorphism and are under strong balancing selection, as their products trigger the adaptive immune response in vertebrates. Here, we assess the allelic diversity and patterns of selection for MHC class I and class II loci in a threatened shorebird with highly flexible mating and parental care behaviour, the Snowy Plover (Charadrius nivosus) across its broad geographic range. We determined the allelic and nucleotide diversity for MHC class I and class II genes using samples of 250 individuals from eight breeding population of Snowy Plovers. We found 40 alleles at MHC class I and six alleles at MHC class II, with individuals carrying two to seven different alleles (mean 3.70) at MHC class I and up to two alleles (mean 1.45) at MHC class II. Diversity was higher in the peptide
HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23. Like other MHC class I molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain (β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8 exons. Exon one encodes the signal peptide, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the transmembrane domain, and exons 6 and 7 encode the cytoplasmic tail. HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells). HLA-E binds a restricted subset of peptides derived ...
Mouse monoclonal HLA Class I antibody [MEM-123] validated for IP, ELISA, Flow Cyt, ICC/IF and tested in Human and Mk. With 2 independent reviews. Immunogen…
MHC Class I antibody LS-C745701 is an unconjugated mouse monoclonal antibody to sheep MHC Class I. Validated for Flow, IHC, IP and WB.
Cytomegaloviruses (CMVs) are expert evaders of nearly every aspect of our immune system. One of these strategies is the downregulation of surface MHC I molecules (major histocompatibility molecules class I). As MHC I molecules present peptides (small fragments) of all proteins generated within the cells to cytotoxic T cells, downregulation of MHC I molecules is an effective way of hiding a viral presence inside the cell from T cells.. Natural killer (NK) cells, lymphocytes that belong to innate immune systems, possess receptors called Ly49 in mice or KIR in humans. These receptors recognize MHC I molecules on the cell surface and inhibit the NK cell, preventing it from uncontrolled killing of cells. The NK cell is thus said to recognize self molecules. When MHC I molecules are downregulated upon virus infection, the NK cell is no longer inhibited by KIR or Ly49 receptors. In particular, when there are other activating signals or inflammation, the NK cell will kill the infected cell with ...
MHC class I molecules are key in the presentation of antigen and initiation of adaptive CD8+ T cell responses. In addition to its classical activity, MHC I may possess nonclassical functions. We have previously identified a regulatory role of MHC I in TLR signaling and antibacterial immunity. However, its role in innate antiviral immunity remains unknown. In this study, we found a reduced viral load in MHC I-deficient macrophages that was independent of type I IFN production. Mechanically, MHC I mediated viral suppression by inhibiting the type I IFN signaling pathway, which depends on SHP2. Cross-linking MHC I at the membrane increased SHP2 activation and further suppressed STAT1 phosphorylation. Therefore, our data revealed an inhibitory role of MHC I in type I IFN response to viral infection and expanded our understanding of MHC I and antigen presentation.
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from |2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P =
Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and ...
Mouse Monoclonal Anti-MHC Class I Antibody (F21-2) [DyLight 488]. Validated: WB, Flow, IHC, IHC-Fr. Tested Reactivity: Avian, Chicken, Turkey. 100% Guaranteed.
Toward demonstrating functional significance for the transmembrane and/or cytoplasmic portions of MICA, we generated a transfectant of Daudi expressing a truncated form of MICA in which the cysteine at position 331 was replaced with a stop codon (Daudi/Class I+/MICA/C331*). The level of cell surface staining of this transfectant with a MICA mAb was similar to that of wild-type MICA in Daudi/Class I+/MICA (Fig. 4, b and c). We tested the susceptibility of these transfectants to NK cell cytotoxicity (Fig. 4 d). A peripheral blood NK cell line was efficiently able to kill untransfected Daudi, which lacks endogenous expression of MHC class I protein, but was inhibited from killing Daudi-expressing MHC class I protein (Daudi/Class I+). In agreement with previous data (5), Daudi-expressing MHC class I protein and MICA was efficiently killed, demonstrating how activation via NKG2D recognition can overcome inhibitory signaling. However, Daudi transfectants expressing MHC class I protein and the ...
NetCTL 1.2 server predicts CTL epitopes in protein sequences. The current version 1.2 is an update to the version 1.0. The version 1.2 expands the MHC class I binding predicition to 12 MHC supertypes including the supertypes A26 and B39. The accuracy of the MHC class I peptide binding affinity is significantly improved compared to the earlier version. Also the prediction of proteasonal cleavage has been improved and is now identical to the predictions obtained by the NetChop-3.0 server. The updated version has been trained on a set of 886 known MHC class I ligands. NOTE. On Aug 16 2006 a minor update to the server has been implemented improving the prediction accuracy for MHC binding. The earlier version of the NetCTL 1.2 server (1.2 beta) is available via the versions history for the server. View the version history of this server. All the previous versions are available on line, for comparison and reference. The method integrates prediction of peptide MHC class I binding, proteasomal C ...
Author SummaryOne of the greatest challenges facing HIV-1 vaccine design today is the formidable capacity of the virus for mutation and adaptation, a characteristic that has contributed to the extensive worldwide genetic variability of HIV-1 strains observed today. On an individual basis, evolutionary selective pressures imposed by each infected persons unique immune response results in the selection and outgrowth of viral
Source data: Western blot scans to accompany Burr et al., An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer, Cancer Cell (2019), https://doi.org/10.1016/j.ccell.2019.08.008
TY - JOUR. T1 - A computational resource for the prediction of peptide binding to Indian rhesus macaque MHC class I molecules. AU - Peters, B.. AU - Bui, H. H.. AU - Sidney, J.. AU - Weng, Z.. AU - Loffredo, J. T.. AU - Watkins, D. I.. AU - Mothé, B. R.. AU - Sette, A.. PY - 2005/11/1. Y1 - 2005/11/1. N2 - Non-human primates, in general, and Indian rhesus macaques, specifically, play an important role in the development and testing of vaccines and diagnostics destined for human use. To date, several frequently expressed macaque MHC molecules have been identified and their binding specificities characterized in detail. Here, we report the development of computational algorithms to predict peptide binding and potential T cell epitopes for the common MHC class I alleles Mamu-A*01, -A*02, -A*11, -B*01 and -B*17, which cover approximately two thirds of the captive Indian rhesus macaque populations. We validated this method utilizing an SIV derived data set encompassing 59 antigenic peptides. Of all ...
BACKGROUND: MICA and MICB (MHC class I-related chain A and B) are polymorphic genes that encode molecules related to MHC class I and are expressed on epithelial cells in response to stress. Incompatible donor MIC antigens can stimulate antibody production in transplant recipients. This study was designed to determine MICB expression in kidney pretransplant and any subsequent changes in expression following transplantation and to correlate changes with inflammatory markers and clinical events. METHODS: Paired renal biopsies obtained from living donor (n=10) and cadaveric allografts (n=50) before and 7 days posttransplant were stained for MICB, leukocytic infiltration, and HLA class II antigens. RESULTS: Variable tubular MICB expression was evident in donor biopsies [high 6/60 (10%), low/negative 13/60 (22%), intermediate 41/60 (68%)]. Following transplantation, MICB was up-regulated on renal tubules of 17/60 (28%) biopsies and was associated with MHC class II antigen induction (P=0.02) and leukocyte
TY - JOUR. T1 - Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia. AU - Kuniholm, Mark H.. AU - Kovacs, Andrea. AU - Gao, Xiaojiang. AU - Xue, Xiaonan. AU - Marti, Darlene. AU - Thio, Chloe L.. AU - Peters, Marion G.. AU - Terrault, Norah A.. AU - Greenblatt, Ruth M.. AU - Goedert, James J.. AU - Cohen, Mardge H.. AU - Minkoff, Howard. AU - Gange, Stephen J.. AU - Anastos, Kathryn. AU - Fazzari, Melissa. AU - Harris, Tiffany G.. AU - Young, Mary A.. AU - Strickler, Howard D.. AU - Carrington, Mary. PY - 2010/5/1. Y1 - 2010/5/1. N2 - Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high-resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multiracial ...
Background: A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known. Methodology/Principal Findings: In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any ...
Background A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8+ T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known. Methodology/Principal Findings In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further
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The basic pattern of MHC variation in fish, with MHC class I versus class II, and polymorphic classical versus nonpolymorphic nonclassical, is similar in fish and mammals. Nevertheless, in many or all teleost fishes, important differences with mammalian or human MHC were observed: (1) The allelic/haplotype diversification levels of classical MHC class I genes tend to be much higher than in mammals; (2) Teleost fish classical MHC class I and class II loci are not linked. The present article summarizes previous studies that performed quantitative trait loci (QTL) analysis for mapping differences in teleost fish disease resistance, and discusses them from MHC point of view. Overall, those studies suggest the possible importance of genomic regions including classical MHC class II and nonclassical MHC class I genes, whereas similar observations were not made for the genomic regions with the highly diversified classical MHC class I alleles. The present study is a review and discussion of the fish MHC
TY - JOUR. T1 - Human cytomegalovirus UL18 utilizes US6 for evading the NK and T-cell responses. AU - Kim, Youngkyun. AU - Park, Boyoun. AU - Cho, Sunglim. AU - Shin, Jinwook. AU - Cho, Kwangmin. AU - Jun, Youngsoo. AU - Ahn, Kwangseog. PY - 2008/8/1. Y1 - 2008/8/1. N2 - Human cytomegalovirus (HCMV) US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I molecules at the cell surface. Cells lacking MHC class I molecules are susceptible to NK cell lysis. HCMV expresses UL18, a MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite a high level of sequence and structural homology between UL18 and MHC class I molecules, surface expression of MHC class I, but not UL18, is down regulated by US6. Here, we describe a mechanism of action by which HCMV UL18 avoids attack by the self-derived TAP inhibitor US6. UL18 abrogates US6 inhibition of ATP binding by TAP and, thereby, restores TAP-mediated peptide translocation. In addition, UL18 together ...
TY - JOUR. T1 - The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells. AU - Davis, Daniel M.. AU - Mandelboim, Ofer. AU - Luque, Isabel. AU - Baba, Eishi. AU - Boyson, Jonathan. AU - Strominger, Jack L.. PY - 1999/4/19. Y1 - 1999/4/19. N2 - Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric ...
For a proper development of the placenta, maternal NK cells should not attack the fetal extravillous cytotrophoblast cells. This inhibition of maternal NK cells is partially mediated via the nonclassical MHC class I molecule HLA-G. Recently, we demonstrated that HLA-G forms disulfide-linked high molecular complexes on the surface of transfected cells. In the present study, we demonstrate that HLA-G must associate with beta(2)m for its interaction with CD85J/leukocyte Ig-like receptor-1 (LIR-1). Although HLA-G free H chain complexes are expressed on the surface, they are not recognized and possibly interfere with CD85J/LIR-1 and HLA-G interaction. The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition. We also show that endogenous HLA-G complexes are expressed on the cell surface. These findings provide novel insights into the delicate interaction between
Major histocompatibility (MHC)-restricted, human immunodeficiency virus type one (HIV-1)-specific, cytotoxic T lymphocytes (CTLs) were detected in the peripheral blood mononuclear cells (PBMCs) of HIV-1-infected individuals. Using a system of autologous B and T lymphoblastoid cell lines infected with recombinant vaccinia vectors (VVs) expressing HIV-1 gene products, we were able to detect HIV-1-specific cytolytic responses in the PBMCs of 88% of HIV-1-seropositive hemophiliac patients in the absence of in vitro stimulation. These cytolytic responses were directed against both HIV-1 envelope and gag gene products. The responses were resistant to natural killer (NK) cell depletion and were inhibited by monoclonal antibodies (MoAbs) to the T cell receptor, CD8 surface antigens, and MHC class I antigens, suggesting a classical MHC class I restricted, virus-specific CTL response.
Somatic cell nuclear transfer (SCNT), or cloning, is a form of artificial reproductive technology that can be used to improve economic traits of domestic animals. However, extreme inefficiency of producing viable offspring via this method is a major limitation. An aggressive immune response at the maternal-fetal interface is an important reason for SCNT pregnancy loss. The goal of this project was to investigate the molecular mechanisms of immune-mediated miscarriage in cloned cattle pregnancies. Many publications hint that immune-mediated miscarriage is associated with abnormal MHC-I expression in the placenta. The regulation of bovine MHC-I genes was systematically studied to identify the cause of abnormal MHC-I expression during immune-mediated miscarriage. We also produced cloned pregnancies to study immune- mediated pregnancy loss. MHC-I and cytokines involved in proinflammatory responses were highly expressed in the placental trophoblast cells of cloned fetuses and in the uterine endometrium of
Major histocompatibility complex class I and II expression on macrophages containing a virulent strain of Brucella abortus measured using green fluorescent protein-expressing brucellae and flow cytometry ...
In neuroblastoma, N-myc suppresses the expression of major histocompatibility complex (MHC) Class I antigens by reducing the binding of a nuclear factor to the enhancer-A element in the MHC Class I gene promoter. We show here that the p50 subunit of NF-kappa B is part of this complex and that expres …
A general method has been developed for measuring the stabilization of class I MHC molecules in extracts of the mutant cell lines .174/T2 and RMA-S. 35S-Met-labeled class I molecules which have been stabilized by peptides in vitro are immunoprecipitated with conformation dependent monoclonal antibodies and electrophoresed on polyacrylamide gels. The heavy and light chains are excised from the dried gel and quantified on a flat bed scintillation counter. The stabilizing effect of peptides on class I molecules in vitro correlates well with peptide binding measured by direct methods and can be therefore used to assess peptide binding affinity. We show that a peptide from HIV-1 gag (which has a high affinity for Db) is a CTL epitope restricted through Db, and also use the assay to analyse the effects of amino acid substitution on peptide affinity. In addition, the effect of a given peptide on a class I molecule within a mixture of human class I molecules can be distinguished by immunoprecipitation with the
TY - JOUR. T1 - High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I: implications for T-Cell receptor engagement and T-cell immunodominance. AU - Tynan, Fleur Elizabeth. AU - Borg, Natalie. AU - Miles, John J. AU - Beddoe, Travis Clarke. AU - Elhassen, Diah. AU - Silins, Sharon L. AU - van Zuylen, Wendy JM. AU - Purcell, Anthony W. AU - Kjer-Nielsen, Lars. AU - McCluskey, James. AU - Burrows, S R. AU - Rossjohn, Jamie. PY - 2005. Y1 - 2005. U2 - 10.1074/jbc.M503060200. DO - 10.1074/jbc.M503060200. M3 - Article. VL - 280. SP - 23900. EP - 23909. JO - Journal of Biological Chemistry. JF - Journal of Biological Chemistry. SN - 1083-351X. IS - 25. ER - ...
Fascinating recent discoveries have focused attention on the nonclassical class I molecules. They can exert their function at most levels of the immune response, being part of both innate and adaptive immune systems. They not only have specialized antigen-presentation functions but also play important immunoregulatory roles: HLA-E regulates natural killer cells by interacting with CD94/NKG2 receptors; the MIC (MHC class I chain related) glycoproteins appear crucial to the activation of gammadelta T cells in the gastrointestinal epithelium; HLA-G may play a role in controlling the immune response to the fetus; and CD1 molecules are important in defense against bacterial infections, as well as in the development and regulation of a subset of NKT cells expressing a highly restricted TCR repertoire; however not all nonclassical class I molecules have an immunological function, as demonstrated by HFE which is implicated in iron metabolism.
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Free resource for searching and exporting immune epitopes. Includes more than 95% of all published infectious disease, allergy, autoimmune, and transplant epitope data.
We have analyzed peptides associated with six human major histocompatibility complex (MHC) class I allomorphs expressed by the U937 cell line. Peptides were isolated by mild acid elution or by MHC class I immunoprecipitation by using W6/32 monoclonal antibody. Eighty-five peptides were sequenced by mass spectrometry, and their putative binding alleles were assigned using bioinformatic tools. Only three peptides isolated by the two approaches were identical, suggesting that the approaches may yield distinct partially overlapping peptide populations. Mild acid treatment-derived peptides manifested overall characteristics suggestive of relatively lower affinity of binding for MHC class I. Interestingly, a large proportion of putative HLA-B*5101-binding peptides was evident among the mild acid treatment-eluted peptides, and to a lesser degree in the affinity-purified peptide pool. These results suggest that HLA-B*5101 may bind a potentially large pool of peptides with relatively lower affinity. We suggest
Clone REA176 recognizes HLA B7 and B27 class I human leukocyte antigens (HLA). Expressed on the surface of most nucleated cells, class I molecules are heterodimeric molecules and consist of a type I integral membrane α heavy chain and soluble β2 microglobulin protein. The extracellular region of the heavy chain further consists of three domains, of which one comprises the peptide binding groove. Antigens binding to class I molecules are 8-10 amino acids long and play an important role in recognition of the virus infected and malignant cells by cytotoxic T lymphocytes (CTLs). In addition, class I molecules interact with NK cell receptors to modulate the activity of NK cells. HLA-B7 is a risk factor for cervical cancer, sarcoidosis, and early-onset spondylarthropathies. HLA-B27 is known for its strong association with inflammatory spondyloarthropathies. It has been also discovered as a protective factor against some severe viral infections.Additional information: Clone REA176 displays negligible binding
The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells. Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 αβ and γδ T cells. Fifty-four MICA and 17 MICB alleles have been described to date. Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest. The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium. We developed a robust, high-resolution PCR-SSP ...
The major histocompatibility complex (MHC) is a collection of genes coding for MHC molecules found on the surface of all nucleated cells of the body. In humans, the MHC genes are also referred to as human leukocyte antigen (HLA) genes. Mature red blood cells, which lack a nucleus, are the only cells that do not express MHC molecules on their surface.. There are two classes of MHC molecules involved in adaptive immunity, MHC I and MHC II (Figure 14.11). MHC I molecules are found on all nucleated cells; they present normal self-antigens as well as abnormal or nonself pathogens to the effector T cells involved in cellular immunity. In contrast, MHC II molecules are only found on macrophages, dendritic cells, and B cells; they present abnormal or nonself pathogen antigens for the initial activation of T cells.. Both types of MHC molecules are transmembrane glycoproteins that assemble as dimers in the cytoplasmic membrane of cells, but their structures are quite different. MHC I molecules are ...
Major histocompatibility complex (MHC) genes encode proteins that initiate adaptive immune responses through the presentation of foreign antigens to T cells. The high polymorphism found at these genes, thought to be promoted and maintained by pathogen-mediated selection, contrasts with the limited number of MHC loci found in most vertebrates. Although expressing many diverse MHC genes should broaden the range of detectable pathogens, it has been hypothesized to also cause deletion of larger fractions of self-reactive T cells, leading to a detrimental reduction of the T cell receptor (TCR) repertoire. However, a key prediction of this TCR depletion hypothesis, that the TCR repertoire should be inversely related to the individual MHC diversity, has never been tested. Here, using high-throughput sequencing and advanced sequencing error correction, we provide evidence of such an association in a rodent species with high interindividual variation in the number of expressed MHC molecules, the bank ...
The x-ray structures of a murine MHC class I molecule (H-2Kb) were determined in complex with two different viral peptides, derived from the vesicular stomatitis virus nucleoprotein (52-59), VSV-8, and the Sendai virus nucleoprotein (324-332), SEV-9. The H-2Kb complexes were refined at 2.3 A for VSV-8 and 2.5 A for SEV-9. The structure of H-2Kb exhibits a high degree of similarity with human HLA class I, although the individual domains can have slightly altered dispositions. Both peptides bind in extended conformations with most of their surfaces buried in the H-2Kb binding groove. The nonamer peptide maintains the same amino- and carboxyl-terminal interactions as the octamer primarily by the insertion of a bulge in the center of an otherwise beta conformation. Most of the specific interactions are between side-chain atoms of H-2Kb and main-chain atoms of peptide. This binding scheme accounts in large part for the enormous diversity of peptide sequences that bind with high affinity to class I ...
Virus or tumor Ag-derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely
A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments.
NetCTLpan 1.1 INSTALLATION INSTRUCTIONS DESCRIPTION The NetCTLpan 1.1 software predicts CTL epitopes in protein sequences. The current version 1.1 is an update to the original NetCTL server that allows for prediction of CTL epitope with restriction to any MHC molecules of known protein sequence. NetCTLpan integrates prediction of peptide MHC class I binding, proteasomal C terminal cleavage and the efficiency of TAP transport. MHC class I binding and proteasomal cleavage is performed using artificial neural networks. TAP transport efficiency is predicted using weight matrix. The method is described in detail in the following article: NetCTLpan - Pan-specific MHC class I epitope predictions. Stranzl T., Larsen M. V., Lundegaard C., Nielsen M. Immunogenetics. 2010 Jun;62(6):357-68. [Epub ahead of print] Apr 9, 2010. More information about the method can be found at: http://www.cbs.dtu.dk/services/NetCTLpan/ DOWNLOAD The netCTLpan 1.1 software package is a property of Center for Biological Sequence ...
Human immunodeficiency computer virus (HIV) Nef is a membrane-associated protein decreasing surface expression of CD4 CD28 and major histocompatibility complex class I on infected cells. by the same mutations in Nef that impact CD4 down-regulation FK866 suggesting common molecular interactions. The ability to down-regulate the human CD8 β-chain was conserved in HIV-1 HIV-2 and simian immunodeficiency computer FK866 virus SIVmac239 Nef and required an intact AP-2 complex. The Nef-mediated internalization of receptors such as CD4 major histocompatibility complex class I CD28 and CD8αβ may contribute to the subversion of the host immune system and progression towards AIDS. The human immunodeficiency computer virus type 1 (HIV-1) Nef protein is usually a 27-kDa protein that is abundantly produced during the early phase of viral gene expression (28 54 Nef is usually posttranslationally altered by phosphorylation and due to irreversible attachment of myristic acid to its N terminus it is targeted ...
Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as non-self neo-antigens by the adaptive immune sys …
POSTDOCTORAL POSITIONS AVAILABLE My laboratory is investigating various aspects of how the immune system carries out surveillance to detect viral infections, cancers and cell death. Among the areas of research are: (1) The alarm signals and the receptors that alert the immune system to potential danger; (2) The mechanisms by which sentinel cells (dendritic cells) acquire and display antigens to CD8 T cells (cross presentation), a process that is essential for immune surveillance of tissues; and, (3) The antigen presentation pathway by which virally infected or cancer cells display their antigens to effector CD8 T cells (MHC class I antigen presentation), a process that is essential for the immune system to detect and eliminate these pathological cells. The laboratory is in a new state of the art research building and part of a very strong and interactive immunology community at UMass Medical School. UMass Medical School is located in Worcester Massachusetts, just outside of Boston. Interested ...
Class I major histocompatibility complex (MHCI) is known to modulate activity-dependent synaptic remodeling in the visual system and to regulate synaptic plasticity in the hippocampus. Here, the authors show that MHCI negatively regulates the density and function of cortical synapses during their initial establishment. Major histocompatibility complex class I (MHCI) molecules modulate activity-dependent refinement and plasticity. We found that MHCI also negatively regulates the density and function of cortical synapses during their initial establishment both in vitro and in vivo. MHCI molecules are expressed on cortical neurons before and during synaptogenesis. In vitro, decreasing surface MHCI (sMHCI) on neurons increased glutamatergic and GABAergic synapse density, whereas overexpression decreased it. In vivo, synapse density was higher throughout development in β2m−/− mice. MHCI also negatively regulated the strength of excitatory, but not inhibitory, synapses and controlled the balance of
Kawashima Y., Pfafferott K., Frater J., Matthews P., Payne R., Addo M., Gatanaga H., Fujiwara M., Hachiya A., Koizumi H., Kuse N., Oka S., Duda A., Prendergast A., Crawford H., Leslie A., Brumme Z., Brumme C., Allen T., Brander C., Kaslow R., Tang J., Hunter E., Allen S., Mulenga J., Branch S., Roach T., John M., Mallal S., Ogwu A., Shapiro R., Prado J.G., Fidler S., Weber J., Pybus O.G., Klenerman P., Ndungu T., Phillips R., Heckerman D., Harrigan P.R., Walker B.D., Takiguchi M., Goulder P. (2009) Adaptation of HIV-1 to human leukocyte antigen class I. Nature ...
Effects of HIV-1 Tat on expression of HLA class I molecules. Dendritic cells transduced with HIV Nef express normal levels of HLA-A and HLA-\b class I molecules
TY - JOUR. T1 - Mamu-A*01/Kb transgenic and MHC Class I knockout mice as a tool for HIV vaccine development. AU - Li, Jinliang. AU - Srivastava, Tumul. AU - Rawal, Ravindra. AU - Manuel, Edwin. AU - Isbell, Donna. AU - Tsark, Walter. AU - La Rosa, Corinna. AU - Wang, Zhongde. AU - Li, Zhongqi. AU - Barry, Peter A. AU - Hagen, Katharine D.. AU - Longmate, Jeffrey. AU - Diamond, Don J.. PY - 2009/4/25. Y1 - 2009/4/25. N2 - We have developed a murine model expressing the rhesus macaque (RM) Mamu-A*01 MHC allele to characterize immune responses and vaccines based on antigens of importance to human disease processes. Towards that goal, transgenic (Tg) mice expressing chimeric RM (α1 and α2 Mamu-A*01 domains) and murine (α3, transmembrane, and cytoplasmic H-2Kb domains) MHC Class I molecules were derived by transgenesis of the H-2KbDb double MHC Class I knockout strain. After immunization of Mamu-A*01/Kb Tg mice with rVV-SIVGag-Pol, the mice generated CD8+ T-cell IFN-γ responses to several known ...
TY - JOUR. T1 - Identification of O-glycosylated decapeptides within the MUC1 repeat domain as potential MHC class I (A2) binding epitopes. AU - Ninkovic, Tanja. AU - Kinarsky, Leo. AU - Engelmann, Katja. AU - Pisarev, Vladimir. AU - Sherman, Simon. AU - Finn, Olivera J.. AU - Hanisch, Franz Georg. N1 - Funding Information: The work was supported by NIH grant 1RO1 CA84106 and the Köln-Fortune Programme (to F.G.H.) and by NIH grant 2PO CA73743 (to O.J.F.).. PY - 2009/11. Y1 - 2009/11. N2 - The MUC1 glycoprotein is considered a tumor antigen due to its over expression and aberrant glycosylation in cancer tissues. The latter results in appearance of new antigenic tumor specific glycopeptides not found on normal glycoforms of the mucin. MUC1 glycopeptides can be presented by APCs on MHC class II molecules to activate glycopeptide specific helper T-cells. No study has yet reported presentation of MUC1 glycopeptides on MHC class I molecules as stimulators of cytotoxic T-cells. In this study we show ...
When T cells, B cells, and natural killer (NK) cells of the immune system interact with target cells, signaling molecules are accumulated in the plasma membrane at structures known as the immunological synapse. Evidence is accumulating that proteins, as well as signals, are transferred between the interacting cells at such contacts. NK cells receive inhibitory signals from cells that express self major histocompatibility complex (MHC) molecules on their surface. Earlier evidence had shown that NK cells can actually acquire MHC class I proteins during interactions with target cells. Now Vanherberghen et al. show that the exchange goes both ways and that NK receptors are transferred to cells that express MHC class I ligands. The authors monitored transfer of biotinylated killer Ig-like receptor (KIR) KIR2DL1 by immunoblotting or green fluorescent protein-tagged receptor by fluorescence-activated cell sorting or laser-scanning confocal microscopy and observed transfer of KIRs. The NK cell receptor ...
In the absence of strategies for reliable induction of antibodies broadly neutralizing human immunodeficiency virus type 1 (HIV-1), vaccine efforts have shifted toward the induction of cell-mediated immunity. Here we describe the construction and immunogenicity of novel T-cell vaccine NS1.HIVA, which delivers the HIV-1 clade A consensus-derived immunogen HIVA on the surface of tubular structures spontaneously formed by protein NS1 of bluetongue virus. We demonstrated that NS1 tubules can accommodate a protein as large as 527 amino acids without losing their self-assembly capability. When injected into BALB/c mice by several routes, chimeric NS1.HIVA tubules induced HIV-1-specific major histocompatibility complex class I-restricted T cells. These could be boosted by modified virus Ankara expressing the same immunogen and generate a memory capable of gamma interferon (IFN-gamma) production, proliferation, and lysis of sensitized target cells. Induced memory T cells readily produced IFN-gamma 230 ...
We found that this phenomenon was associated with the different susceptibility of human and mouse NK cells to autologous tumour cell-induced NK cell abnormalities (NKCA). The latter includes CD16 down-regulation and NK cell depletion. Induction of NKCA by leukaemia and solid tumour cells was influenced neither by IL2 treatment nor by HLA class I antigen expression, but was abrogated by a 10 day culture. Following a 10 day of PBMCs culture, NK cells became resistant to leukaemia and solid tumor cell induced NKCA but maintained their cytotoxic activity. Actinomycin D restored the susceptibility of long term NK (LTNK) cells to NKCA suggesting that the generation of resistance to NKCA required RNA transcription. TAPI-0, a functional analogue of the tissue inhibitor of metalloproteinases (TIMP) 3 inhibited cancer cell induced NKCA underlying a role for a restricted number of metalloproteinases in the generation of this phenomenon. Finally, we found an association of TIMP3 gene and protein ...
The purpose of this study was to investigate whether IgG, non-donor-specific anti-HLA class I antibodies (HLAabI) detected after renal transplantation recognize immunogenic amino acid triplets expressed on the foreign graft. In addition, we sought to evaluate the effect of these antibodies as well as other posttransplant HLAabI on graft outcome. Posttransplant sera from 264 renal recipients were tested for the presence of IgG HLAabI and HLA class II-specific alloantibodies (HLAabII) by ELISA. The HLAMatchmaker computer algorithm was used to define the HLA class I non-donor-specific antibodies, which seem to recognize immunogenic amino acid triplets. Donor-specific triplet antibodies (DSTRab) were detected in 16 of 22 (72.7%) recipients based on at least one HLA-A or -B mismatched antigen with the donor. DSTRab were found either without (n = 7) or with (n = 9) HLA donor-specific antibodies (HLA-DSA). The presence of DSTRab alone in the periphery was associated with acute rejection, whereas the ...
TY - JOUR. T1 - Class I HLA folding and antigen presentation in β2- microglobulin-defective daudi cells. AU - Martayan, Aline. AU - Sibilio, Leonardo. AU - Tremante, Elisa. AU - Monaco, Elisa Lo. AU - Mulder, Arend. AU - Fruci, Doriana. AU - Cova, Agata. AU - Rivoltini, Licia. AU - Giacomini, Patrizio. PY - 2009/3/15. Y1 - 2009/3/15. N2 - To present virus and tumor Ags, HLA class I molecules undergo a complex multistep assembly involving discrete but transient folding intermediates. The most extensive folding abnormalities occur in cells lacking the class I L chain subunit, called β2-microglobulin (β2m). Herein, this issue was investigated taking advantage of eight conformational murine mAbs (including the prototypic W6/32 mAb) to mapped H chain epitopes of class I molecules, four human mAbs to class I alloantigens, as well as radioimmunoprecipitation, in vitro assembly, pulse-chase, flow cytometry, and peptide-pulse/ELISPOT experiments. We show that endogenous (HLA-A1, -A66, and -B58) as ...
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