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Results for “Major Histocompatibility Complex”

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At least 145 records · Page 8Linked to original sources

PubMed1998

Analysis of Gag-specific cytotoxic T lymphocytes in simian immunodeficiency virus-infected rhesus monkeys by cell staining with a tetrameric major histocompatibility complex class I-peptide complex.

A tetrameric recombinant major histocompatibility complex (MHC) class I-peptide complex was used as a staining reagent in flow cytometric analyses to quantitate and define the phenotype of Gag-specific cytotoxic T lymphocytes (CTLs) in the peripheral blood of simian immunodeficiency virus macaque (SIVmac)-infected rhesus monkeys. The heavy chain of the rhesus monkey MHC class I molecule Mamu-A*01 and beta2-microglobulin were refolded in the presence of an SIVmac Gag synthetic peptide (p11C, C-M) representing the optimal nine-amino acid peptide of Mamu-A*01-restricted predominant CTL epitope to create a tetrameric Mamu-A*01/p11C, C-M complex. Tetrameric Mamu-A*01/p11C, C-M complex bound to T cells of SIVmac-infected, Mamu-A*01(+), but not uninfected, Mamu-A*01(+), or infected, Mamu-A*01(-) rhesus monkeys. Specific staining of peripheral blood mononuclear cells (PBMC) from SIVmac-infected, Mamu-A*01(+) rhesus monkeys was only found in the cluster of differentiation (CD)8alpha/beta+ T lymphocyte subset and the percentage of CD8alpha/beta+ T cells in the peripheral blood of four SIVmac-infected, Mamu-A*01+ rhesus monkeys staining with this complex ranged from 0.7 to 10.3%. Importantly, functional SIVmac Gag p11C-specific CTL activity was seen in sorted and expanded tetrameric Mamu-A*01/p11C, C-M complex-binding, but not nonbinding, CD8alpha/beta+ T cells. Furthermore, the percentage of CD8alpha/beta+ T cells binding this tetrameric Mamu-A*01/p11C, C-M complex correlated well with p11C-specific cytotoxic activity as measured in both bulk and limiting dilution effector frequency assays. Finally, phenotypic characterization of the cells binding this tetrameric complex indicated that this lymphocyte population is heterogeneous. These studies indicate the power of this approach for examining virus-specific CTLs in in vivo settings.

Animals↗

PubMed2025

Major histocompatibility complex class IIB disassortative mate choice in a genetically monogamous seabird.

Among species reproducing sexually, mating strategies represent a major component of individual fitness. The major histocompatibility complex (MHC) is an extremely diverse set of genes responsible for immunological recognition and defence against pathogens. Although dissimilarity between mates at the major histocompatibility complex has been proposed to drive mate choice through increased offspring pathogen resistance, evidence is mixed. In addition, explorations of the role of the major histocompatibility complex in other mating strategies, such as divorce, are rare. We investigated whether dissimilarity at the major histocompatibility complex class IIB is associated with mate choice and divorce probability in the genetically monogamous black-legged kittiwake (Rissa tridactyla). We found that first-time male breeders, as well as divorced males, were paired with females more dissimilar at the major histocompatibility complex class IIB than expected under random mating. We did not find evidence for mate choice based on major histocompatibility complex class IIB dissimilarity when considering females. In addition, in the studied population, divorce probability was very low compared with other populations and did not significantly vary with the dissimilarity of the pair at the major histocompatibility complex class IIB. Our results pave the way to a better understanding of the complex role of major histocompatibility complex dissimilarity in mating decisions of species displaying mutual choice and biparental care.

Animals↗

PubMed2000

The major and a minor class II beta-chain (B-LB ) gene flank the Tapasin gene in the B-F /B-L region of the chicken major histocompatibility complex.

We have identified the major histocompatibility complex class II beta-chain (B-LB) genes present in the B-F/B-L region of the B complex of nine well-characterized lines of chickens and have cleared up much of the confusion concerning numbers and location of B-LB genes in this region. By amplifying DNA sequences between adjacent genes, we found two B-LB genes that lie on either side of Tapasin. The dominantly expressed 'major' B-LB gene in all haplotypes lies between Tapasin and RING-3, and belongs to the B-LBII family of class II beta-chain genes. The poorly expressed 'minor' B-LB gene in all haplotypes lies between B-lec1 and Tapasin, and belongs either to the B-LBII family or to the previously unmapped B-LBVI family of class II beta-chain genes. The data suggest that the B-LBII and B-LBVI genes are two lineages of B-LB genes and we propose that they all be termed B-LB genes. The location of a third B-LB gene in the B12 haplotype (and possibly other haplotypes as well) has yet to be determined. The structural organization and expression of the class II beta-chain genes in the B-F/B-L region is similar to that of chicken class I (B-F) genes, one functional result of which is differential resistance to disease and response to vaccines.

Animals↗

PubMed1985

Expression in L cells of transfected class I genes from the mouse major histocompatibility complex.

One of the major surprises of the molecular analysis of major histocompatibility complex (MHC) genes is the large number of class I (K/D)-related sequences in the genome. Both restriction fragment length polymorphisms and cosmid cloning experiments showed them all to be closely linked to the MHC. Until now little information was available concerning either their expression or recognition by the immune system. Here we report that these non-K/D genes can provoke antibody responses and be recognized by cytolytic T cells. Immunization of C3H mice with L cells transfected with class I genomic clones resulted in antisera that reacted preferentially with cells from strain B10.P (the gene donor). Thus, these genes can be expressed by L cells. These products were recognized by cytolytic T cells produced by mixed lymphocyte culture with B10.P stimulators. One gene, represented in clone lambda 3a, was chosen for further analysis. A restriction fragment length polymorphism, detected between B10.P (KpDp) and B10.F(14R) (KbDp) and between B10 (KbDb) and B10.F(13R) (KpDb), has enabled us to map the lambda 3a sequence to the D or Tla region. Restriction endonuclease mapping of the lambda 3a clone shows that the gene is intact and that, although many restriction sites are conserved, the gene in lambda 3a differs from other class I genes. When the lambda 3a clone was transfected into mouse L cells, a new product was expressed. Cells expressing this product (designated L3a cells) were killed by primary D-end-reactive, allospecific cytolytic T lymphocytes. The L3a cells were unreactive with monoclonal antibodies specific for the Kp,Dp,Qa-2, Tla.3, and Tla.5 molecules.

Animals↗

PubMed1993

Regulated expression of the major histocompatibility complex class I genes.

The major histocompatibility complex (MHC) class I gene products are known to play a fundamental role in foreign antigen presentation to the cellular immune system. Much attention has been directed to the study of MHC class I gene expression as a means to understanding the processes by which MHC class I-mediated immune responses are regulated. Two areas of considerable interest have emerged, including regulation at the levels of transcriptional control and antigenic peptide-induced transport of MHC class I molecules. With an emphasis on these major areas of research, we review recent developments on the molecular and biochemical mediators and events of MHC class I gene regulation.

Animals↗

PubMed2003

N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA.

Major histocompatibility complex (MHC) class II molecules play an essential role for the cellular immune response by presenting peptide antigens to CD4(+) T cells. MHC class II molecules and genes show a highly complex expression pattern, which is orchestrated through a master regulatory factor, called CIITA (class II transactivator). CIITA controls MHC class II expression not only qualitatively, but also quantitatively, and has therefore a direct influence on the CD4 T cell-dependent immune response. CIITA is itself tightly regulated not only on the transcriptional level, but as we show here also on the protein level. CIITA is subjected to a very rapid protein turnover and shows a half-life of about 30 min. Inhibition of degradation by proteasome inhibitors and the identification of ubiquitylated CIITA intermediates indicate that the degradation of CIITA is mediated by the ubiquitin-proteasome system. We identified two regions mediating degradation within the N-terminal domain of CIITA. N-terminal fusions or deletions stabilized CIITA, indicating that the N termini contribute to degradation. Several non-functional CIITA mutants are partially stabilized, but we provide evidence that transcriptional activity of CIITA is not directly linked to degradation.

Amino Acid Sequence↗

PubMed1993

Exon-intron organization of fish major histocompatibility complex class II B genes.

Major histocompatibility complex (Mhc) molecules bind self and foreign peptides and present them to lymphocytes for recognition. Activation of lymphocytes by Mhc-bound foreign peptides leads to specific immune response against parasites. The Mhc genes have been studied extensively in mammals and birds but much less in other vertebrate classes. In this communication we provide the first description of the exon-intron organization of class II beta-chain-encoding genes from the teleost fish Aulonocara hansbaenschi, family Cichlidae. Each of the genes consists of six exons, E1 through E6, encoding the leader peptide (E1), beta 1 domain (E1+E2), beta 2 domain (E3+E4), connecting peptide (E5), transmembrane region (E5), cytoplasmic domain (E5+E6), and the 3' untranslated region (E6). The exons are separated by relatively short introns, the length of the longest intron being 1.3 kilobase pairs. An important difference between these and all other known class II B genes is that the beta 2 domain-encoding exon is split by an intron 97 base pairs in length. The intron is absent in other teleost fishes such as Brachydanio rerio. A change in the 3' splice site of intron 4 in some of the genes of A. hansbaenschi and of another cichlid fish, Cyphotilapia frontosa, has produced two extra codons at the 5' end of exon 5. Comparison of the A. hansbaenschi coding sequences with those of C. frontosa has revealed a concentration of variability in exon 2 and part of exon 3. Taken together, these observations provide evidence for the existence in cichlid fishes of at least two class II B loci which are functionally equivalent to the corresponding loci in mammals. The exon-intron organization and sequence similarities indicate that the two loci arose by duplication from a common ancestral gene.

Amino Acid Sequence↗

PubMed1989

Multiple sclerosis: oligodendrocytes in active lesions do not express class II major histocompatibility complex molecules.

The expression of major histocompatibility complex (MHC) molecules by oligodendrocytes has been proposed as evidence for their involvement in the multiple sclerosis (MS) lesion although the literature on the subject is controversial and based largely upon observations in vitro. With a modified immunocytochemical procedure on 1 micron epoxy sections, the present study has examined the expression of class II MHC molecules (Ia) on cells within actively demyelinating lesions in a central nervous system biopsy from a case of acute MS. White Ia was readily demonstrable on microglial cells and astrocytes, it was never detected on adjacent surviving oligodendrocytes. Unexpectedly, in parallel sections, the oligodendrocytes stained positively for myelin-associated glycoprotein, a marker for immature oligodendrocytes. The unequivocal lack of Ia expression by oligodendrocytes in MS makes it unlikely that they serve as immunomodulators in lesion pathogenesis.

Adolescent↗

PubMed1997

Studies on the interaction of T-cells with major histocompatibility complex class II antigens.

1. Major histocompatibility complex class II antigens have the central role in the immune response of 'presenting' antigenic peptide to CD4+ T-cells. This interaction with a T-cell's receptor may result in activation, but, if recognition occurs without collateral molecular interactions which cause 'co-stimulation', these T-cells will be tolerized. 2. In the light of current interest in muscle cell transplantation, a transformed myoblast, TE671, phenotypically comparable to untransformed cells, transfected to express class II, was studied as a stable model of antigen presentation by muscle cells. These cells failed to activate T-cells but induced tolerance. 3. The DR alpha chain is unusual being the only non-polymorphic classical class II polypeptide, raising the question of its functional contribution. To this end, several single polypeptide constructs were generated with contributions from different class II alpha-chains. On this basis, it was established that DR alpha makes significant contributions to peptide binding and that its alpha 2 domain is also important in T-cell recognition, possibly through CD4 binding. 4. One implication of the lack of polymorphism of DR alpha may be that it has a wider range of pairing partners, possibly including beta chains of different isotypes. To address this, it is planned to use transfectants expressing only a mixed isotype pair to generate T-cell clones in vitro. These reagents would be useful tools to detect whether such mixed pairs exist physiologically. In this paper, the development of a system is described which will allow this question to be addressed.

Antigen Presentation↗

PubMed1987

Sequence-specific interactions of nuclear factors with conserved sequences of human class II major histocompatibility complex genes.

All class II major histocompatibility complex genes contain two highly conserved sequences, termed X and Y, within the promoter regions(s), which may have a role in regulation of expression. To study trans-acting factors that interact with these sequences, sequence-specific DNA binding activity has been examined by the gel electrophoresis retardation assay using the HLA-DQ2 beta gene 5' flanking DNA and nuclear extracts derived from various cell types. Several specific protein-binding activities were found using a 45-base-pair (bp) HinfI/Sau96I (-142 to -98 bp) and a 38-bp Sau96I/Sau96I (-97 to -60 bp) fragment, which include conserved sequence X (-113 to -100 bp) and conserved sequence Y (-80 to -71 bp), respectively. Competition experiments, methylation interference analysis, and DNase I foot-printing demonstrated that distinct proteins in a nuclear extract of Raji cells (a human B lymphoma line) bind to sequence X, to sequence Y, and to DNA 5' of the X sequence (termed sequence W). The factor binding site in the W sequence is also found to be conserved among beta-chain genes and is suggested to be a gamma-interferon control region.

B-Lymphocytes↗

PubMed1989

Altered growth of a human neuroendocrine carcinoma line after transfection of a major histocompatibility complex class I gene.

The major histocompatibility complex (MHC) class I molecules are known to serve as recognition elements for cytotoxic T cells in mediating the rejection of transplanted tumors. We demonstrate that MHC molecules may have nonimmune functions in modulating tumor cell growth in addition to their classical role in antitumor immunity. A human neuroendocrine carcinoma cell line, COLO 320, with low levels of endogenous class I expression was transfected with the murine H-2Ld gene. Eleven independent stable clones were established, four containing only pRSV-neo and seven also containing varying copy numbers of the transfected Ld gene. The ability of the different clones to grow as colonies in soft agar correlated strongly with the relative amounts of Ld antigen expression (r = 0.89; P less than 0.001). There was a weaker correlation between increased clonogenic ability and higher levels of Ld mRNA (r = 0.67; P less than 0.05). There was no correlation between clonogenic ability and relative expression of amplified c-myc gene or of integrated pRSV-neo. Furthermore, in nude mice, Ld antigen expression was associated with increased formation of metastatic lung colonies 6 weeks after intravenous injection of 10(5) cells. These observations are consistent with the concept that MHC class I antigens may have a role in modulating the growth potential of certain tumor cells independent of their involvement in immune responses.

Adenocarcinoma↗

PubMed1997

Distinct intracellular compartments involved in invariant chain degradation and antigenic peptide loading of major histocompatibility complex (MHC) class II molecules.

Major histocompatibility complex (MHC) class II molecules are transported to intracellular MHC class II compartments via a transient association with the invariant chain (Ii). After removal of the invariant chain, peptides can be loaded onto class II molecules, a process catalyzed by human leukocyte antigen-DM (HLA-DM) molecules. Here we show that MHC class II compartments consist of two physically and functionally distinct organelles. Newly synthesized MHC class II/Ii complexes were targeted to endocytic organelles lacking HLA-DM molecules, where Ii degradation occurred. From these organelles, class II molecules were transported to a distinct organelle containing HLA-DM, in which peptides were loaded onto class II molecules. This latter organelle was not directly accessible via fluid phase endocytosis, suggesting that it is not part of the endosomal pathway. Uptake via antigen-specific membrane immunoglobulin resulted however in small amounts of antigen in the HLA-DM positive organelles. From this peptide-loading compartment, class II-peptide complexes were transported to the plasma membrane, in part after transit through endocytic organelles. The existence of two separate compartments, one involved in Ii removal and the other functioning in HLA-DM-dependent peptide loading of class II molecules, may contribute to the efficiency of antigen presentation by the selective recruitment of peptide-receptive MHC class II molecules and HLA-DM to the same subcellular location.

Antibodies, Bacterial↗

PubMed1994

The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules.

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.

Animals↗

PubMed2002

Two distinct pathways mediated by PA28 and hsp90 in major histocompatibility complex class I antigen processing.

Major histocompatibility complex (MHC) class I ligands are mainly produced by the proteasome. Herein, we show that the processing of antigens is regulated by two distinct pathways, one requiring PA28 and the other hsp90. Both hsp90 and PA28 enhanced the antigen processing of ovalbumin (OVA). Geldanamycin, an inhibitor of hsp90, almost completely suppressed OVA antigen presentation in PA28alpha(-/-)/beta(-/-) lipopolysaccharide blasts, but not in wild-type cells, indicating that hsp90 compensates for the loss of PA28 and is essential in the PA28-independent pathway. In contrast, treatment of cells with interferon (IFN)-gamma, which induces PA28 expression, abrogated the requirement of hsp90, suggesting that IFN-gamma enhances the PA28-dependent pathway, whereas it diminishes hsp90-dependent pathway. Importantly, IFN-gamma did not induce MHC class I expressions in PA28-deficient cells, indicating a prominent role for PA28 in IFN-gamma-stimulated peptide supply. Thus, these two pathways operate either redundantly or specifically, depending on antigen species and cell type.

Amino Acid Sequence↗

PubMed1999

Orientation and positional mapping of the subunits of the multicomponent transcription factors RFX and X2BP to the major histocompatibility complex class II transcriptional enhancer.

Major histocompatibility complex class II genes contain a common complex enhancer that allows for their coordinate regulation. The X box element of the enhancer cooperatively binds the multisubunit transcription factors RFX and X2BP. RFX is an essential class II transcription factor and contains three distinct proteins: RFX5, RFX-B/Ank and RFXAP. X2BP, a CREB/ATF family transcription factor, most likely binds as a homodimer. A site-specific protein-DNA photocrosslinking assay was used to investigate the interactions of the subunits of RFX and X2BP with X box DNA. Two of the RFX subunits, RFX5 and RFX-B/Ank, were found to bind defined sites within the X1 half of the X box. The third RFX subunit, RFXAP, made extensive X1 box contacts. The subunits of X2BP made contacts with the edges of the X2 half of the X box in a manner consistent with other bZIP transcription factor contact patterns. The resulting map provides specific base pair contacts and subunit orientation with respect to the DNA sequence of the RFX-X2BP-X box complex. Our results suggest possible stoichiometry of the RFX subunits and potential interaction between RFX-B/Ank and RFXAP with one of the subunits of X2BP.

Base Sequence↗

PubMed1990

Evolutionary relationships of class II major-histocompatibility-complex genes in mammals.

The major histocompatibility complex (MHC) class II molecule consists of noncovalently associated alpha and beta chains. In mammals studied so far, the class II MHC can be divided into a number of regions, each containing one or more alpha-chain genes (A genes) and beta-chain genes (B genes), and it has been known for some time that orthologous relationships exist between genes in corresponding regions from different mammalian species. A phylogenetic analysis of DNA sequences of class II A and B genes confirmed these relationships; but no such orthologous relationship was observed between the B genes of mammals and those of birds. Thus, the class II regions have diverged since the separation of birds and mammals (approximately 300 Mya) but before the radiation of the placental mammalian orders (60-80 Mya). Comparison of the phylogenetic trees for A and B genes revealed an unexpected characteristic of DP-region genes: DPB genes are most closely related to DQB genes, whereas DPA chain genes are most closely related to DRA-chain genes. Thus, the DP region seems to have originated through a recombinational event which brought together a DQB gene and a DRA gene (perhaps approximately 120 Mya). The 5' untranslated region of all class II genes includes sequences which are believed to be important in regulating class II gene expression but which are not conserved in known pseudogenes. These sequences are conserved to an extraordinary degree in the human DQB1 gene and its mouse homologue A beta 1, suggesting that regulation of expression of this locus may play a key role in expression of the entire class II MHC.

Amino Acids↗

PubMed2004

Association of intracellular proteins with folded major histocompatibility complex class I molecules.

The major histocompatibility complex (MHC) class I molecule is responsible for presenting peptide antigens at the cell surface for recognition by cytotoxic T lymphocytes. Several chaperone molecules interact with the MHC class I heavy chain and release when the MHC groove folds around peptide. Two additional proteins, invariant chain and amyloid precursor-like protein 2 (APLP2), interact specifically and stably with MHC class I molecules that have folded peptide-binding grooves. Invariant chain and APLP2 also affect MHC class I cell-surface expression, and so may play a part in MHC class I trafficking. Association of APLP2 with the MHC class I molecule appears to be regulated by a viral protein, the adenovirus E3/19K protein. Analysis of the interactions of these proteins with each other and with MHC class I will clarify how presentation of antigens by MHC class I is controlled by events that occur subsequent to MHC class I folding.

Adenoviridae↗

PubMed2000

Structural and functional dissection of human cytomegalovirus US3 in binding major histocompatibility complex class I molecules.

The human cytomegalovirus US3, an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, forms a complex with major histocompatibility complex (MHC) class I molecules and retains them in the ER, thereby preventing cytolysis by cytotoxic T lymphocytes. To identify which parts of US3 confine the protein to the ER and which parts are responsible for the association with MHC class I molecules, we constructed truncated mutant and chimeric forms in which US3 domains were exchanged with corresponding domains of CD4 and analyzed them for their intracellular localization and the ability to associate with MHC class I molecules. All of the truncated mutant and chimeric proteins containing the luminal domain of US3 were retained in the ER, while replacement of the US3 luminal domain with that of CD4 led to cell surface expression of the chimera. Thus, the luminal domain of US3 was sufficient for ER retention. Immunolocalization of the US3 glycoprotein after nocodazole treatment and the observation that the carbohydrate moiety of the US3 glycoprotein was not modified by Golgi enzymes indicated that the ER localization of US3 involved true retention, without recycling through the Golgi. Unlike the ER retention signal, the ability to associate with MHC class I molecules required the transmembrane domain in addition to the luminal domain of US3. Direct interaction between US3 and MHC class I molecules could be demonstrated after in vitro translation by coimmunoprecipitation. Together, the present data indicate that the properties that allow US3 to be localized in the ER and bind MHC class I molecules are located in different parts of the molecule.

Endoplasmic Reticulum↗