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 - 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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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...
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 ...
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 ...
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 ...
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. ...
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 ...
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…
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 ...
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 ...
... 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
Author Summary HLA class I molecules are expressed on the cell surface of almost all cells of the human body in complex with short fragments (peptides) of cytosolic proteins, thereby providing a snapshot of the intracellular state of a cell to circulating CD8+ T cells. Several processes are involved in shaping the peptide ligand repertoire of an HLA class I molecule, which generally represents only a small fraction of the proteins available in the cytosol. In our work we addressed protein sampling by HLA class I molecules to answer two questions: 1) Which proteins are sampled by the antigen processing pathway and why, and 2) which peptides of a given protein are picked to represent the source protein on the cell surface? To this end we quantified the contribution of each process involved in peptide processing and presentation individually and combined them into a logistic regression model. This simple model enabled us to predict the sampling probability of self proteins and may aid in the identification
Clone REA230 recognizes a monomorphic epitope on MHC class I molecules, HLA A, B, and C. MHC class I molecules are expressed by all human nucleated cells and are involved in presentation of peptide ligands on the cell surface for recognition by cytotoxic T cells. Additional information: Clone REA230 displays negligible binding to Fc receptors. - USA
In contrast to the predetermination model, TCR-dependent models of effector fate specification have been advanced, which posit that a gradient of TCR signaling from weakest to strongest is involved in the generation of IL-17, IFN-γ, and innate γδ T cells, respectively (Fig. 1B, 1C). Efforts to test this model entailed manipulation of either the γδ TCR-selecting ligand or signaling molecules downstream from the TCR.. Although few γδ T cell ligands are known, one of the best-studied γδ T cell ligands is the nonclassical MHC class I molecule T10/T22, which requires β2-microglobulin (β2m) for its surface expression (43). To assess the role of T10/T22 ligand engagement in effector fate specification, B2m−/− mice were used, in which surface expression of T10/22 is indirectly attenuated. One caveat is that β2m deficiency does not completely eliminate the expression of T10/22 on the cell surface (22, 29), and the low levels of T10/T22 that remain might influence the development of ...
Clone REA672 recognizes the class I human leukocyte antigens (HLA) B and C. 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, one of which 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. Additional information: Clone REA672 displays negligible binding to Fc receptors. - USA
Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1-9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a ...
Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1 ...
The major histocompatibility complex (MHC) class I chain-related A (MICA) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8+ T cells. The single nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low avidity (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyse them in view of new data on the functional consequences of this polymorphism. It has been shown recently, that the MICA-129Met variant elicits a stronger NKG2D signalling, resulting in more degranulation and IFN-γ production in NK cells and in a faster co-stimulation of CD8+ T cells than the MICA-129Val
Antigen presenting cells (APCs) ingest pathogens and digest their proteins into antigens. Pathogen engulfment activates professional APCs, causing the cells to migrate to lymph nodes where they encounter T cells. They display these antigens on their cell surface major histocompatibility complex (MHC) receptors. T cell receptor complexes recognize these antigen-MHC complexes and other necessary stimulatory macromolecules, inducing them to promote the appropriate immunological responses. Dendritic cells, one major class of professional APC, reside in tissues exposed to the external environment and represent the first line of defense against invading pathogenic organisms. Derived from hematopoietic progenitor cells, dendritic cells only differentiate and mature after contact with an antigen. Additional professional APC classes include macrophages and B cells, whereas fibroblasts and certain epithelial cell subtypes become non-professional APCs under the appropriate conditions. A full description of ...
Abacavir is a nucleoside reverse transcriptase inhibitor used for combination antiretroviral therapy for treating human immunodeficiency virus (HIV) infection. An adverse effect from abacavir is a treatment-limiting hypersensitivity reaction, which can be severe and potentially life-threatening. Abacavir-induced hypersensitivity reaction has been associated with the presence of the major histocompatibility complex class I allele HLA-B*5701. A screening test for the HLA-B*5701 allele can assist clinicians to identify patients who are at risk of developing a hypersensitivity reaction to abacavir.. ...
Objectives HLA-B*5701 is a major histocompatibility complex class I allele associated with an immunologically-mediated hypersensitivity reaction to abacavir.
Interestingly, weve found that MHC class I molecules are not static entities; they move in a specific way, allowing them to act as immunological "sentinels". And because there are many different variants of the MHC class I molecule in the human population, they all have slightly different propensities when it comes to selecting cancer peptides. By collecting this information and building it into computer programmes, we hope to be able to predict exactly which cancer-derived peptides will boost the killer T cells that do the most harm to the tumour, without damaging normal tissue. This will provide a basis for designing better cancer vaccines and may even allow us to select patients who will respond well to checkpoint blockade immunotherapy.. ...
Cytotoxic T cells (also known as Tc, killer T cell, or cytotoxic T-lymphocyte (CTL)) express CD8 coreceptor are a population of T cells that are specialised for inducing programmed cell death of other cells. Cytotoxic T cells regularly patrol all body cells to maintain the organismal homeostasis. Whenever they encounter signs of disease, caused for example by the presence of viruses or intracellular bacteria or a transformed tumor cell, they initiate processes to destroy the potentially harmful cell.[1] All nucleated cells in the body (along with platelets) display class I major histocompatibility complex (MHC-I molecules). Antigens generated endogenously within these cells are bound to MHC-I molecules and presented on the cell surface. This antigen presentation pathway enables the immune system to detect transformed or infected cells displaying peptides from modified-self (mutated) or foreign proteins.[4][5]. In the presentation process, these proteins are mainly degraded into small peptides by ...
Major Histocompatibility Complex (MHC) glycoproteins are heterodimeric cell surface receptors that function to present antigen peptide fragments to T cells responsible for cell-mediated immune responses. MHC molecules can be subdivided into two groups on the basis of structure and function: class I molecules present intracellular antigen peptide fragments (~10 amino acids) on the surface of the host cells to cytotoxic T cells; class II molecules present exogenously derived antigenic peptides (~15 amino acids) to helper T cells. MHC class I and II molecules are assembled and loaded with their peptide ligands via different mechanisms. However, both present peptide fragments rather than entire proteins to T cells, and are required to mount an immune response.. Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as ...
The purpose of this paper was to demonstrate the feasibility and describe the difficulties of setting up a large MSC bank from allogeneic donors for use in academic clinical trials. The constitution of a human third-party MSC bank from screened healthy volunteer donors and the follow-up of different aspects of this activity since 2007 are developed. Results from 68 large scale clinical expansions are described and discussed. Methods of generating clinical-grade MSCs have already been described by other groups but, to our knowledge, this is the first paper describing such a large and detailed banking experience [14, 15].. The absence of co-stimulatory molecules and human leucocyte antigen (HLA) class II molecules, as well as low HLA class I expression on MSCs, make them ideal for allogeneic use. MSC produced and used in our clinical trials are of allogeneic origin but do not seem to elicit immune responses. Indeed, HLA-mismatched MSC manufactured by the same process were shown to be weakly ...
Genetically engineered temperature-sensitive class I HLA mutants are provided which can be used in a method to obtain peptides which are bound to MHC class I molecules on the surfaces of cells that are transfected with the mutant genes.
The dynamics of T cell responses have been extensively studied during single virus infection of naïve mice. During a viral infection, viral antigen is presented in the context of MHC class I molecules on the surface of infected cells. Activated CD8 T cells that recognized viral antigens mediate clearance of virus through lysis of these infected cells. We hypothesize that the balance between the replicating speed of the virus and the efficiency at which the T cell response clears the virus is key in determining the disease outcome of the host. Lower T cell efficiency and delayed viral clearance can lead to extensive T cellmediated immunopathology and death in some circumstances. To examine how the efficiency of the immune response would impact immunopathology we studied several viral infection models where T cell responses were predicted to be less than optimal: 1. a model of co-infection with two viruses that contain a crossreactive epitope, 2. a viral infection model where a high dose infection is
Purpose: We hypothesized that T-cell immune interaction affects tumor development and thus clinical outcome. Therefore, we examined the clinical impact of human leukocyte antigen (HLA) class I tumor cell expression and regulatory T-cell (Treg) infiltration in breast cancer.. Experimental Design: Our study population (N = 677) is consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed, paraffin-embedded tumor tissue was immunohistochemically stained using HCA2, HC10, and Foxp3 monoclonal antibodies.. Results: HLA class I expression was evaluated by combining results from HCA2 and HC10 antibodies and classified into three groups: loss, downregulation, and expression. Remarkably, only in patients who received chemotherapy, both presence of Treg (P = 0.013) and higher HLA class I expression levels (P = 0.002) resulted in less relapses, independently of other variables. Treg and HLA class I were not of influence on clinical ...
This chapter focuses on the generation and maintenance of the acquired immune response against bacterial pathogens and the pathological effects that may occur if this response is left uncontrolled or actively disregulated. The chapter outlines the general mechanisms of acquired immunity, and then, using specific examples, discusses how various bacterial pathogens induce and modulate this response. Lymphocytes communicate with high endothelial venules via receptor-ligand interactions, which induce lymphocyte transmigration. These adhesion molecules include selectins, integrins, and members of the immunoglobulin (Ig) superfamily. For infections with intracellular bacteria in particular, CD4 T cells dominate both the induction and effector phases of the immune response. Peptides that are presented by major histocompatibility (MHC) class I molecules are generated from endogenous proteins or proteins that are secreted into the cytoplasm. In light of this, CD8 T-cell responses are central to the immune