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At least 847 records · Page 47Linked to original sources
PubMed1988

Selection of class I MHC-restricted peptides with the strip-of-helix hydrophobicity algorithm.

A strip-of-helix hydrophobicity algorithm to predict class II MHC-restricted peptides, on the basis of their structural similarity to an amphipathic, alpha-helix in Ii, also predicted peptides which were presented to cytotoxic T-cells by class I MHC molecules. This algorithm ranked peptides according to mean Kyte-Doolittle hydrophobicity values of amino acids at positions n, n + 4, n + 7, n + 11, n + 14 and n + 18 in a sequence which when coiled as a putative alpha-helix, had the indicated residues in an axial strip along one side of the helix. Sequences selected for highly scoring, hydrophobic strips were required to have at least 1 of the 4 adjacent strips scoring more negatively than -1 in the strip-of-helix hydrophobicity index and the entire sequence could contain no prolines. This algorithm predicted the class I MHC-restricted, T-cell-presented peptides in sequences of 4 proteins from which some class I MHC-restricted, T-cell-presented sequences had been experimentally determined. Since both class I and class II MHC-restricted peptides could be identified with this algorithm, one can propose that: (1) foreign peptide-binding sites (desetopes) of the class I and class II MHC molecules are structurally similar; and (2) any one T-cell-presented peptide can be presented by some specific allele of both a class I and a class II MHC antigen.

Algorithms↗
PubMed1995

A tricyclic ring system replaces the variable regions of peptides presented by three alleles of human MHC class I molecules.

BACKGROUND: Cytotoxic T-lymphocytes (CTLs) recognize complexes of short peptides with major histocompatibility complex (MHC) class I molecules. MHC molecules are polymorphic, and the products of different MHC alleles bind to different subsets of peptides. This is due to differences in the shape of the peptide-binding groove on the surface of the MHC protein, especially the 'pockets' into which anchor residues at each end of the peptide fit. Non-peptidic ligands for class I molecules may be useful clinically. RESULTS: By applying computer-aided design methods guided by X-ray structures, we designed and synthesized several MHC class I ligands, based on known peptide ligands, in which the tricyclic, aromatic compound phenanthridine replaced the central amino acids of the peptides. These semi-peptidic fluorescent ligands bound with high affinity and with allelic specificity to the peptide-binding groove of different MHC class I molecules, forming crystallizable complexes. CONCLUSIONS: Specificity for binding to different MHC class I molecules can be imparted to the common phenanthridine element by judicious choice of terminal peptidic elements from either nonamer or decamer peptides. The phenanthridine-based ligands have a long bound half-life, as do antigenic peptides.

Alleles↗
PubMed2004

Modification of peptide interaction with MHC creates TCR partial agonists.

We report the creation of TCR partial agonists by the novel approach of manipulating the interaction between immunogenic peptide and MHC. Amino acids at MHC anchor positions of the I-E(k)-restricted hemoglobin (64-76) and moth cytochrome c (88-103) peptides were exchanged with MHC anchor residues from the low affinity class II invariant chain peptide (CLIP), resulting in antigenic peptides with altered affinity for MHC class II. Several low affinity peptides were identified as TCR partial agonists, as defined by the ability to stimulate cytolytic function but not proliferation. For example, a peptide containing methionine substitutions at positions one and nine of the I-E(k) binding motif acted as a partial agonist for two hemoglobin-reactive T cell clones (PL.17 and 3.L2). The identical MHC anchor substitutions in moth cytochrome c (88-103) also created a partial agonist for a mCC-reactive T cell (A.E7). Thus, peptides containing MHC anchor modifications mediated similar T cell responses regardless of TCR fine specificity or antigen reactivity. This data contrasts with the unique specificity among individual clones demonstrated using traditional altered peptide ligands containing substitutions at TCR contact residues. In conclusion, we demonstrate that altering the MHC anchor residues of the immunogenic peptide can be a powerful method to create TCR partial agonists.

Amino Acid Sequence↗
PubMed2004

MHC-peptide binding is assisted by bound water molecules.

Water plays an important role in determining the high affinity of epitopes to the class I MHC complex. To study the energy and dynamics of water interactions in the complex we performed molecular dynamics simulation of the class I MHC-HLA2 complex bound to the HIV reverse transcriptase epitope, ILKEPVHGV, and in the absence of the epitope. Each simulation was extended for 5ns. We studied the processes of water penetration in the interface between MHC and peptide, and identified 14 water molecules that stay bound for periods longer than 1ns in regions previously identified by crystallography. These water molecules in the interface perform definite "tasks" contributing to the binding energy: hydrogen bond bridges between MHC and peptide and filling empty spaces in the groove which enhance affinity without contributing to epitope specificity. We calculate the binding energy for interfacial water molecules and find that there is an overall gain in free energy resulting from the formation of water clusters at the epitope-MHC interface. Water molecules serving the task of filling empty spaces bind at the interface with a net gain in entropy, relative to their entropy in bulk. We conclude that water molecules at the interface play the role of active mediators in the MHC-peptide interaction, and might be responsible for the large binding affinity of the MHC complex to a large number of epitope sequences.

Amino Acid Sequence↗
PubMed2006

Inhibition of MHC class II gene expression in uveal melanoma cells is due to methylation of the CIITA gene or an upstream activator.

Most cells with an intact interferon-gamma receptor and signaling pathway are able to express MHC class II molecules when treated with cytokines such as interferon-gamma and tumor necrosis factor-a. Interestingly, primary uveal melanocytes and most ocular melanoma cells are resistant to interferon-gamma mediated induction of class II MHC genes. This unusual phenotype is hypothesized to be germane to the immune-privileged status to the eye. Via a series of experiments, we have probed the molecular basis of this class II MHC resistant phenotype. We have analyzed the methylation status of the gene encoding the class II transactivator (CIITA), and asked whether treatment of class II MHC resistant ocular melanoma cells with the demethylating agent 5'-azacytidine can restore interferon-gamma inducibility of these class II MHC genes in these cells. The data obtained suggest that the specific blockade in cytokine-induced class II MHC gene expression is due to a suppression of the gene encoding the class II transactivator (CIITA). Treatment with 5' azacytidine restores the ability of these cells to express class II MHC genes upon interferon-gamma treatment. Whilst this is reminiscent of what occurs in another immune-privileged tissue--the placental trophoblast--we show here that silencing of the CIITA gene in uveal melanocytes either involves methylation of distinct nucleotides from those detected in trophoblasts, or involves an upstream activator of CIITA gene expression.

Azacitidine↗
PubMedDate not supplied

Analysis of MHC class I expression in equine trophoblast cells using in situ hybridization.

Down-regulation of major histocompatibility complex (MHC) genes by trophoblast cells is considered to be a primary mechanism preventing maternal immune rejection of the fetal-placental unit in mammalian pregnancy by rendering these cells, which form the primary barrier between mother and fetus, relatively non-antigenic. In situ hybridization with probes encoding human and horse MHC class I genes was used to characterize the pattern of MHC class I mRNA expression in the various forms of horse trophoblast. Strong hybridization signals were observed in the invasive trophoblast cells of chorionic girdle tissue. In contrast, no hybridization signal specific for MHC class I mRNA transcripts was observed in the descendent endometrial cup trophoblast cells. In the non-invasive trophoblast cells of the allantochorion, no hybridization signals specific for horse MHC class I mRNA transcripts were consistently detected. In parallel to the in vivo results, strong hybridization signals were observed in the small, mononuclear cells present in chorionic girdle cell explant cultures, but not in the population of large binucleate cells corresponding to endometrial cup cells. The results obtained using in situ hybridization are consistent with the hypothesis that expression of MHC class I genes may be controlled at the transcriptional level in horse invasive and non-invasive trophoblast cells, and suggest that down-regulation of MHC class I antigen expression in endometrial cup cells may be accomplished by the same mechanisms in vivo and in vitro.

Animals↗
PubMed1998

Retroelements in the human MHC class II region.

Molecular genetic studies of the human major histocompatibility complex (MHC) have led to the identification of more than 200 genes. Besides the large number of genes in the MHC, densely clustered areas of retroelements have been identified. These include short and long interspersed elements (SINEs and LINEs), and human endogenous retroviruses (HERVs). The presence of retroelements in the MHC provides a clear example of how these elements affect the genome plasticity of the host. Comparative analyses of these retroelements have proven highly useful in evolutionary studies of the MHC. Recently, HERV-encoded superantigens have been implicated as candidate autoimmune genes in type I diabetes and multiple sclerosis. In addition, genetic analyses have revealed that autoimmune diseases show strong associations with MHC class II genes. The intriguing correlations between retroviral encoded antigens, MHC class II genes and the development of autoimmune disease merit intense future investigations of retroelements, in particular those endogenous retroviruses located in the MHC class II region proper.

Antigens↗
PubMed1996

The effect of eicosanoids on the expression of MHC genes in cultured human colon cancer cells and mouse colonocytes in vivo.

Eicosanoids have been implicated in the pathogenesis of cancer and are known to regulate the expression of antigens of the major histocompatibility complex (MHC). In human colon cancer, we have recently observed that: (a) the expression of MHC class I and II antigens are markedly reduced; and (b) the levels of PGE2, but not of PGF2 alpha and LTB4, are elevated compared to histologically normal mucosa. Therefore, we investigated the effect of PGE2, PGF2 alpha and LTB4 on the regulation of MHC class I antigens in two human colon adenocarcinoma cell lines and in a murine model of colon cancer. None of these eicosanoids had any significant effect on the expression of MHC class I antigens in the human colonocytes or the transcription rate of class I genes, with the exception of LTB4 which only modestly suppressed the transcription rate. Similarly, 16, 16-dimethyl-PGE2 had no effect on the expression of MHC class I genes in the colonocytes of BALB/c mice treated with the carcinogen dimethylhydrazine. We conclude that PGE2, PGF2 alpha and LTB4 did not affect the expression of MHC class I antigens in cultured human colon adenocarcinoma cells, and 16, 16-dimethyl PGE2 did not affect their expression in mice, even when mice were treated with a colon carcinogen. Thus, these eicosanoids are an unlikely regulator of the observed underexpression of MHC class I antigens in human colon cancer.

16,16-Dimethylprostaglandin E2↗
PubMed2000

Nitric oxide inhibits INFgamma-induced increases in CIITA mRNA abundance and activation of CIITA dependent genes--class II MHC, Ii and H-2M. Class II TransActivator.

BACKGROUND: Nitric oxide (NO) has been recently implicated as a powerful inhibitor of immune responses during allograft rejection, and some autoimmune and infectious diseases. We previously showed that one potential regulatory effect of NO is inhibition of IFNgamma-stimulated expression of Class II MHC on macrophages. Activation of this gene is mediated by the "Class II TransActivator" (CIITA). We now ask whether NO inhibits CIITA and thus the family of genes regulated by CIITA--Class II MHC, Ii, and H-2M. The latter two genes participate in antigen processing and formation of the cell-surface peptide-Class II MHC complex. METHODS: Murine macrophages--both peritoneal macrophages and the RAW264.7 macrophage line--were stimulated in vitro with IFNgamma. NO production was measured by the Greiss reagent. Transcription of Class II MHC was measured by nuclear run-on assay. mRNA abundance of Class II MHC, Ii, H-2M, and CIITA was measured by Northern blotting and RT-PCR. RESULTS: NO inhibits IFNgamma-induced increases in the abundance and transcription of the Class II MHC Ab gene. The increases in mRNA abundance of CIITA, Ii, and H-2M are also inhibited. As a control, we found that NO did not inhibit LPS-induce increases in TNFalpha mRNA abundance. CONCLUSIONS: NO inhibits IFNgamma-induced increases in CIITA, and thus inhibits the CIITA-regulated genes: Class II MHC, Ii, and H-2M. Early during rejection, NO production by macrophages may result after stimulation by IFNgamma produced by CD4+ T cells, and be an effector of allograft damage. High concentrations of NO may then act as a feedback inhibitor which decreases antigen presentation by macrophages and thus decreases CD4 T cell activation.

Animals↗
PubMed1999

Mice lacking all conventional MHC class II genes.

MHC class II (MHC-II) molecules play a central role in the selection of the T cell repertoire, in the establishment and regulation of the adaptive immune response, and in autoimmune deviation. We have generated knockout mice lacking all four of the classical murine MHC-II genes (MHCII(Delta/Delta) mice), via a large (80-kilobase) deletion of the entire class II region that was engineered by homologous recombination and Cre recombinase-mediated excision. These mice feature immune system perturbations like those of Aalpha and Abeta knockout animals, notably a dearth of CD4(+) lymphocytes in the thymus and spleen. No new anatomical or physiological abnormalities were observed in MHCII(Delta/Delta) mice. Because these animals are devoid of all classical MHC-II chains, even unpaired chains, they make excellent recipients for MHC-II transgenes from other species, avoiding the problem of interspecies cross-pairing of MHC-II chains. Therefore, they should be invaluable for engineering "humanized" mouse models of human MHC-II-associated autoimmune disorders.

Animals↗
PubMed1995

The two novel MHC class II transactivators RFX5 and CIITA both control expression of HLA-DM genes.

MHC-encoded HLA-DMA and -DMB molecules are atypical MHC chains that play an essential role in antigen presentation by MHC class II molecules. They resemble both MHC class I and II molecules but are not expressed at the cell surface. From the study of MHC class II regulatory mutants, it was found recently that two novel transactivators, CIITA and RFX5, are essential for the control of MHC class II gene expression. We report here that CIITA and RFX5, although operating at different levels of transcriptional control, are also both essential regulators of HLA-DMA and -DMB genes. This is true for both the constitutive and the inducible mode of DM gene expression. Indeed, both CIITA and RFX5 cDNA can correct the HLA-DMA and -DMB gene expression defect in the respective regulatory mutants. The involvement of these two transcription factors accounts for the coordinate expression of MHC class II and HLA-DM, two sets of molecules that perform quite different functions in the overall process of antigen presentation.

Cell Line↗
PubMed1995

CIITA activates the expression of MHC class II genes in mouse T cells.

It has long been a puzzle that MHC class II molecules are expressed in human T cells after activation but not in mouse T cells; this expression is believed to play a role in the cell mediated immune response. Recently the MHC class II transactivator (CIITA) has been reported to be a major regulatory factor for both the constitutive and IFN inducible expression of MHC class II genes. Here we show that human T cells expressing MHC class II have CIITA transcripts while MHC class II-negative human T cells and mouse T cells do not. The expression of MHC class II genes in mouse T cells can be reconstituted upon transfection with the human CIITA cDNA. These data indicate that the expression of CIITA explains the expression or lack of expression of MHC class II in human and mouse T cells respectively.

Animals↗
PubMed2006

Expression of RAB4B, a protein governing endocytic recycling, is co-regulated with MHC class II genes.

The small GTPase RAB4 regulates endocytic recycling, a process that contributes to Major Histocompatibility Complex (MHC)-mediated antigen presentation by specialized antigen presenting cells (APC) of the immune system. The gene encoding the RAB4B isoform of RAB4 was singled out by two complementary genome-wide screens. One of these consisted of a computer scan to identify genes containing characteristic MHC class II-related regulatory sequences. The second was the use of chromatin immunoprecipitation coupled to microarrays (ChIP-on-chip) to identify novel targets of a transcriptional co-activator called the MHC class II transactivator (CIITA). We show that the RAB4B gene is regulated by a typical MHC class II-like enhancer that is controlled directly by both CIITA and the multiprotein transcription factor complex known as the MHC class II enhanceosome. RAB4B expression is thus activated by the same regulatory machinery that is known to be essential for the expression of MHC class II genes. This molecular link between the transcriptional activation of RAB4B and MHC class II genes implies that APC boost their antigen presentation capacity by increasing RAB4-mediated endocytic recycling.

Binding Sites↗
PubMed2001

Enzymatically mediated engineering of multivalent MHC class II-peptide chimeras.

We previously reported the genetic engineering of the first soluble, bivalent major histocompatibility complex (MHC) class II-peptide ligand for T-cell receptor (TCR). This ligand binds stably and specifically to cognate T-cells and exhibits immunomodulatory effects in vitro and in vivo. The increase in valence of MHC class II-peptide ligands was shown to parallel their avidity for cognate TCRs and potency in stimulating cognate T-cells. We describe a new enzymatic method to increase the valence of MHC-peptide ligands by cross-linking the N-glycan moieties of dimeric MHC II-peptide units through a flexible, bifunctional polyethylene glycol linker. Using this method, we generated covalently stabilized tetravalent and octavalent MHC II-peptide ligands which bound stably and specifically to cognate TCR and preserved their structural integrity in blood and lymphoid organs for 72 h. Depending on the TCR/CD4 occupancy and degree of TCR/CD4 co-clustering, the multivalent MHC II-peptide ligands polarized efficiently the antigen-specific CD4(+) T-cells toward type 2 cell differentiation or induced T-cell anergy and apoptosis. The enzymatically mediated engineering of multivalent MHC-peptide ligands for cognate TCRs may provide rational grounds for the development of new therapeutic agents endowed with strong modulatory effects on antigen-specific T-cells.

Animals↗
PubMed2000

MHC class II pseudogene and genomic signature of a 32-kb cosmid in the house finch (Carpodacus mexicanus).

Large-scale sequencing studies in vertebrates have thus far focused primarily on the genomes of a few model organisms. Birds are of interest to genomics because of their much smaller and highly streamlined genomes compared to mammals. However, large-scale genetic work has been confined almost exclusively to the chicken; we know little about general aspects of genomes in nongame birds. This study examines the organization of a genomic region containing an Mhc class II B gene in a representative of another important lineage of the avian tree, the songbirds (Passeriformes). We used a shotgun sequencing approach to determine the sequence of a 32-kb cosmid insert containing a strongly hybridizing Mhc fragment from house finches (Carpodacus mexicanus). There were a total of three genes found on the cosmid clone, about the gene density expected for the mammalian Mhc: a class II Mhc beta-chain gene (Came-DAB1), a serine-threonine kinase, and a zinc finger motif. Frameshift mutations in both the second and third exons of Came-DAB1 and the unalignability of the gene after the third exon suggest that it is a nonfunctional pseudogene. In addition, the identifiable introns of Came-DAB1 are more than twice as large as those of chickens. Nucleotide diversity in the peptide-binding region of Came-DAB1 (Pi = 0.03) was much lower than polymorphic chicken and other functional Mhc genes but higher than the expected diversity for a neutral locus in birds, perhaps because of hitchhiking on a selected Mhc locus close by. The serine-threonine kinase gene is likely functional, whereas the zinc finger motif is likely nonfunctional. A paucity of long simple-sequence repeats and retroelements is consistent with emerging rules of chicken genomics, and a pictorial analysis of the "genomic signature" of this sequence, the first of its kind for birds, bears strong similarity to mammalian signatures, suggesting common higher-order structures in these homeothermic genomes. The house finch sequence is among a very few of its kind from nonmodel vertebrates and provides insight into the evolution of the avian Mhc and of avian genomes generally.

Animals↗
PubMed1994

T cell differentiation and generation of the antigen-specific T cell repertoire in man: observations in MHC class II deficiency.

The circulating T cell pool of an MHC class II-deficient patient was shown to lack the MHC class II-specific T cell functions. This was demonstrated by the absence of MHC class II-specific alloreactive T cells and a substantially decreased number of circulating CD4+ lymphocytes. The patient's T cells did respond to an allostimulus, although the restriction pattern of this reaction remains speculative. The function and distribution of peripheral T cell subsets from the patient resemble findings in MHC class II-deficient mice, which also lack interaction of T cell precursors with MHC class II-bearing accessory cells during thymic differentiation. Our data support the concept that T cell differentiation in humans is similar, and that the human MHC-restricted T cell repertoire depends on prior interaction of T cell precursors with self MHC.

Base Sequence↗
PubMed2002

The PML gene is not involved in the regulation of MHC class I expression in human cell lines.

The promyelocytic leukemia gene, PML, is a growth and transformation suppressor. An additional role for PML as a regulator of major histocompatibility complex (MHC) class I antigen presentation has been proposed in a murine model, which would account for evasion from host immunity of tumors bearing malfunctioning PML, such as acute promyelocytic leukemia. Here we investigated a possible role of PML for the control MHC class I expression in human cells. PML function was perturbed in human cell lines either by PML/RAR alpha transfection or by PML- specific RNA interference. Impairment of wild-type PML function was proved by a microspeckled disassembly of nuclear bodies (NBs), where the protein is normally localized, or by their complete disappearance. However, no MHC class I down-regulation was observed in both instances. We next constructed a PML mutant, PML mut ex3, that is a human homolog of the murine PML mutant, truncated in exon 3, that was shown to down-regulate murine MHC class I. PML mut ex3 transfected in human cell lines exerted a dominant-negative effect since no PML molecules were detected in NBs but, instead, in perinuclear and cytoplasmic larger dot-like structures. Nevertheless, no down-regulation of MHC class I expression was evident. Moreover, neither transfection with PML mut ex3 nor PML-specific RNA interference affected the ability of gamma-interferon to up-regulate MHC class I expression. We conclude that, in human cell lines, PML is not involved directly in the regulation of MHC class I expression.

Amino Acid Sequence↗
PubMed2002

Analysis of cDNA coding MHC class II beta chain of the chimpanzee (Pan troglodytes).

The chimpanzee (Pan troglodytes, Patr) is the closest zoological living relative of humans and shares approximately 98.6% genetic homology to human beings. Although major histocompatibility complex (MHC) plays a critical role in T cell-mediated immune responses in vertebrates, the information on Patr MHC remains at a relatively poor level. Therefore, we attempted to isolate Patr MHC class II genes and determine their nucleotide sequences. The cDNAs encoding Patr MHC class II DP, DQ and DR beta chains were isolated from the cDNA library of a chimpanzee B lymphocyte cell line Bch261. As a result of screening, the clone 6-3-1 as a representative of Patr DP clone, clone 30-1 as a Patr DQ clone, and clones 4-7-1 and 55-1 having different sequences as Patr DR clones were detected. The clone 6-3-1 consisted of 1,062 nucleotides including an open reading frame (ORF) of 777 bp. In the same way, clone 30-1 consisted of 1,172 nucleotides including ORF of 786 bp, clones 4-7-1 and 55-1 consisted of 1,163 nucleotides including ORF of 801 bp. Except for five nucleotide changes, clones 4-7-1 and 55-1 were the same sequence. By comparison with the nucleotide sequences already reported on chimpanzee MHC class II beta 1 genes, clones 6-3-1, 30-1, 4-7-1 and 55-1 were classified as PatrDPB1*16, PatrDQB1*0302, PatrDRB1*0201 and PatrDRB1*0204, respectively. This is the first report to describe complete cDNA sequences of Patr DP and DQ molecules. The nucleotide sequence data of Patr MHC class II genes obtained in this study will be useful for the genotyping of Patr MHC class II genes in individual chimpanzees.

Amino Acid Sequence↗