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PubMed1992

Diversity of T-cell receptors in virus-specific cytotoxic T lymphocytes recognizing three distinct viral epitopes restricted by a single major histocompatibility complex molecule.

Cytotoxic T lymphocytes (CTL) recognize virus peptide fragments complexed with class I major histocompatibility complex (MHC) molecules on the surface of virus-infected cells. Recognition is mediated by a membrane-bound T-cell receptor (TCR) composed of alpha and beta chains. Studies of the CTL response to lymphocytic choriomeningitis virus (LCMV) in H-2b mice have revealed that three distinct viral epitopes are recognized by CTL of the H-2b haplotype and that all of the three epitopes are restricted by the Db MHC molecule. The immunodominant Db-restricted CTL epitope, located at LCMV glycoprotein amino acids 278 to 286, was earlier noted to be recognized by TCRs that consistently contained V alpha 4 segments but had heterogeneous V beta segments. Here we show that CTL clones recognizing the other two H-2Db-restricted epitopes, LCMV glycoprotein amino acids 34 to 40 and nucleoprotein amino acids 397 to 407 (defined in this study), utilize TCR alpha chains which do not belong to the V alpha 4 subfamily. Hence, usage of V alpha and V beta in the TCRs recognizing peptide fragments from one virus restricted by a single MHC molecule is not sufficiently homogeneous to allow manipulation of the anti-viral CTL response at the level of TCRs. The diversity of anti-viral CTL likely provides the host with a wider option for attacking virus-infected cells and prevents the emergence of virus escape mutants that might arise if TCRs specific for the virus were homogeneous.

Amino Acid Sequence↗
PubMed1987

Functional expression of a heterologous major histocompatibility complex class I gene in transgenic mice.

The regulated expression of major histocompatibility complex class I antigens is essential for assuring proper cellular immune responses. To study H-2 class I gene regulation, we have transferred a foreign class I gene to inbred mice and have previously shown that the heterologous class I gene was expressed in a tissue-dependent manner. In this report, we demonstrate that these mice expressed the transgenic class I molecule on the cell surface without any alteration in the level of endogenous H-2 class I antigens. Skin grafts from transgenic mice were rapidly rejected by mice of the background strain, indicating that the transgenic antigen was expressed in an immunologically functional form. As with endogenous H-2 class I genes, the class I transgene was inducible by interferon treatment and suppressible by human adenovirus 12 transformation. Linkage analysis indicated that the transgene was not closely linked to endogenous class I loci, suggesting that trans-regulation of class I genes can occur for class I genes located outside the major histocompatibility complex.

Animals↗
PubMed1993

Antisense oligonucleotides specific for regulatory factor RFX-1 inhibit inducible but not constitutive expression of all major histocompatibility complex class II genes.

The regulation of major histocompatibility complex (MHC) class II genes expression, which can be constitutive, inducible or both, is a crucial aspect of the control of an immune response. It involves binding of various regulatory factors to cis-acting sequences of MHC class II promoters. Antisense oligonucleotides specific for RFX-1, a regulatory factor binding to the functionally essential X box motive of MHC class II promoters, were designed to study the role of RFX-1 in the various modes of MHC class II regulation and explore the possibility of experimentally modulating the level of expression of MHC class II genes by transcriptional intervention. RFX-1 antisense oligonucleotides were first tested in cell-free translation, selected for an inhibitory effect on RFX-1 in vitro translation and then assayed in cell cultures for an effect on human histocompatibility leukocyte antigen (HLA) class II expression. We show that an RFX-1 specific antisense oligonucleotide drastically inhibits induction of HLA-DR,-DQ, and -DP molecules by interferon gamma in monocytic cells. Unexpectedly, the same agent has no effect on the constitutive expression of the same genes either in these cells or in B lymphocytes, indicating an uncoupling of the constitutive and inducible modes of class II regulation. This transient and reversible experimental modulation of MHC class II expression in live cells by transcriptional intervention provides a new tool to study the function of class II molecules in various biological models.

B-Lymphocytes↗
PubMed2002

Molecular characterization of the Pb recombination hotspot in the mouse major histocompatibility complex class II region.

In the mouse major histocompatibility complex (MHC) class II region, meiotic recombination breakpoints are clustered in four specific sites known as hotspots. Here we reveal the primary structure of a hotspot near the Pb gene. A total of 12 crossover points were found to be confined to a 15-kb DNA segment of the Pb pseudogene. Moreover, the crossover points are concentrated in a 341-bp segment, which includes a part of exon 4 and intron 4 of the Pb gene. All four MHC hotspots appear to be located within genes or at the 3' end of genes, contrasting with characterized hotspots in budding yeast, which are mostly located at the 5'-promoter regions of genes. The Pb hotspot has several consensus motifs, an octamer transcription factor-binding sequence, the B-motif-like transcription factor-binding sequence, and tandem repeats of tetramer sequence-all of which are shared by the other three hotspots. Systematic analysis of the public database demonstrated that the full motif set occurs rarely in the nucleotide sequence of the entire MHC class II region. All results suggest that the motif set has an indispensable role in determining their site specificity.

Animals↗
PubMed2004

Evolutionary and functional perspectives of the major histocompatibility complex class I antigen-processing machinery.

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8+ T cells, providing the basis for immune recognition of pathogen-infected cells. Peptides generated mainly by proteasomes in the cytosol are transported into the lumen of the endoplasmic reticulum by transporters associated with antigen processing (TAP). The maturation of MHC class I molecules is controlled by a number of accessory proteins and chaperones that are to a varying degree dedicated to the assembly of MHC class I. Several newly characterised proteins have been demonstrated to play important roles in this process. This review focuses on the functional relationship and evolutionary history of the antigen-processing machinery (APM) components and MHC class I itself. These are of great interest for further elucidating the origin of the immune system and understanding the mechanisms of antigen presentation and immunology in general.

ATP-Binding Cassette Transporters↗
PubMed2005

Haplotype characterization of transcribed ovine major histocompatibility complex (MHC) class I genes.

The ovine major histocompatibility complex (MHC) remains poorly characterized compared with those of other livestock species. Molecular genetic analysis of the bovine MHC has revealed considerable haplotype and allelic diversity that earlier serological analysis had not detected. To develop cellular and molecular tools to support development of vaccines against intracellular pathogens of sheep, we have undertaken a molecular genetic analysis of four distinct ovine MHC haplotypes carried by two heterozygous Blackface rams. We have identified 12 novel class I transcripts and used a class I sequence-specific genotyping system to assign each of these transcripts to individual haplotypes. Using a combination of phylogenetic analysis, haplotype and transcript expression data, we identified at least four distinct polymorphic class I MHC loci, three of which appear together in a number of combinations in individual haplotypes. The haplotypes were further characterized at the highly polymorphic Ovar-DRB1 locus, allowing selection of the progeny of the two founder rams for the establishment of an MHC-defined resource population.

Amino Acid Sequence↗
PubMed1976

Differential cellular immune responsiveness to systems of the major histocompatibility complex.

Antigens determined by genes of the major histocompatibility complex can be divided into two systems" the LD (lymphocyte-defined or L determinant) and SD (serologically defined or S determinant) antigens. This division is based on the differential cellular responsiveness to these two sets of antigens of two subpopulations of T lymphocytes: a proliferating helper cell responds primarily to the LD antigens while a cytotoxic T lymphocyte responds most strongly to the SD antigens.

Animals↗
PubMed2002

Functional expression of a bovine major histocompatibility complex class I gene in transgenic mice.

Major histocompatibility complex (MHC) class I restricted cellular immune responses play an important role in immunity to intracellular pathogens. By binding antigenic peptides and presenting them to T cells, class I molecules impose significant selection on the targets of immune responses. Candidate vaccine antigens for cellular immune responses should therefore be analysed in the context of MHC class I antigen presentation. Transgenic mice expressing human MHC (HLA) genes provide a useful model for the identification of potential cytotoxic T lymphocyte (CTL) antigens. To facilitate the analysis of candidate CTL vaccines in cattle, we have produced transgenic mice expressing a common bovine MHC (BoLA) class I allele. The functional BoLA-A11 gene, carried on a 7 kb genomic DNA fragment, was used to make transgenic mice by pronuclear microinjection. Three transgenic mouse lines carrying the BoLA-A11 gene were established. Expression of the BoLA-A11 gene was found in RNA and the A11 product could be detected on the surface of spleen and blood cells. Functional analysis of the A11 transgene product, and its ability to act as an antigen presenting molecules in the mouse host will be discussed.

Animals↗
PubMed1992

Proteasome subunits encoded by the major histocompatibility complex are not essential for antigen presentation.

Major histocompatibility complex (MHC) class I molecules bind and deliver peptides derived from endogenously synthesized proteins to the cell surface for survey by cytotoxic T lymphocytes. It is believed that endogenous antigens are generally degraded in the cytosol, the resulting peptides being translocated into the endoplasmic reticulum where they bind to MHC class I molecules. Transporters containing an ATP-binding cassette encoded by the MHC class II region seem to be responsible for this transport. Genes coding for two subunits of the '20S' proteasome (a multicatalytic proteinase) have been found in the vicinity of the two transporter genes in the MHC class II region, indicating that the proteasome could be the unknown proteolytic entity in the cytosol involved in the generation of MHC class I-binding peptides. By introducing rat genes encoding the MHC-linked transporters into a human cell line lacking both transporter and proteasome subunit genes, we show here that the MHC-encoded proteasome subunit are not essential for stable MHC class I surface expression, or for processing and presentation of antigenic peptides from influenza virus and an intracellular protein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Enterobacterial infection modulates major histocompatibility complex class I expression on mononuclear cells.

Major histocompatibility complex (MHC) class I expression is reduced in several viral infections, but it is not known whether the same happens during infections caused by intracellular enterobacteria. In this study, the expression of MHC class I antigens on peripheral blood mononuclear cells (PBMC) from 16 patients with Salmonella, Yersinia, or Klebsiella infection was investigated. During or after the acute infection, the expression of MHC class I antigens was markedly decreased in eight patients, all with genotype HLA-B27, and six out of eight with reactive arthritis (ReA). A significant decrease of monomorphic MHC class I was found in three patients, of HLA-B27 in eight (P<0.05) and of HLA-A2 in two. However, patients negative for the HLA-B27 genotype, or healthy HLA-B27-positive individuals, did not have a significant decrease of MHC class I antigens. During the decreased expression on the cell surface, intracellular retention of MHC class I antigens was observed, whereas HLA-B27 mRNA levels did not vary significantly. This is the first evidence that enterobacterial infection may down-regulate expression of MHC class I molecules in vivo and that down-regulation is predominant in patients with the HLA-B27 genotype.

Adolescent↗
PubMed2003

Possible mechanisms underlying development of transfusion-related acute lung injury: roles of anti-major histocompatibility complex class II DR antibody.

Anti-major histocompatibility complex (anti-MHC) antibodies (Abs) and antipolymorphonuclear neutrophil (anti-PMN) Abs are generally considered as the main causes of the development of transfusion-related acute lung injury (TRALI), which is one of the most severe and sometimes lethal side effects of transfusion. These Abs are postulated to activate recipient's leucocytes, resulting in the release of soluble factors such as reactive oxygen species and detrimental cytokines and chemokines. The harmful effects on the lung tissues and resident leucocytes of these malignant factors are suspected to be profoundly involved in TRALI reactions. Several reports have indicated the principle effect of biologically active lipids on the pathogenesis of TRALI. However, the precise mechanisms of TRALI development remain unclear. To resolve this issue, we have been investigating cytokines that induce continuous inflammation of the lungs, specifically focusing on the cytokines derived from activated PMNs. We observed that the granulocyte-macrophage colony-stimulating factor (GM-CSF) markedly enhances the expression of MHC class II DR in PMNs. Moreover, MHC class II DR-expressing PMNs were also proved to express a high-affinity receptor for immunoglobulin E (IgE) (FcepsilonRI) and to produce tumour necrosis factor-alpha, interferon-gamma and interleukin-18 following a challenge with an anti-MHC class II DR monoclonal Ab (MoAb) or anti-DR antiserum. It is strongly suggested that amongst various inflammatory mediators, at least these three cytokines may contribute to the duration of inflammatory reactions in the lungs. Furthermore, FcepsilonRI expression, in GM-CSF-treated PMNs, suggests the involvement of PMNs in IgE-mediated immune reactions.

Cytokines↗
PubMed2000

Primitive synteny of vertebrate major histocompatibility complex class I and class II genes.

Major histocompatibility complex (MHC) class I and class II molecules bind to and display peptidic antigens acquired from pathogens that are recognized by lymphocytes coordinating and executing adaptive immune responses. The two classes of MHC proteins have nearly identical tertiary structures and were derived from a common ancestor that probably existed not long before the emergence of the cartilaginous fish. Class I and class II genes are genetically linked in tetrapods but are not syntenic in teleost fish, a phylogenetic taxon derived from the oldest vertebrate ancestor examined to date. Cartilaginous fish (sharks, skates, and rays) are in the oldest taxon of extant jawed vertebrates; we have carried out segregation analyses in two families of nurse sharks and one family of the banded houndshark that revealed a close linkage of class IIalpha and beta genes both with each other and with the classical class I (class Ia) gene. These results strongly suggest that the primordial duplication giving rise to classical class I and class II occurred in cis, and the close linkage between these two classes of genes has been maintained for at least 460 million years in representatives of most vertebrate taxa.

Amino Acid Sequence↗
PubMed1995

Tolerance to amino acid variations in peptides binding to the major histocompatibility complex class I protein H-2Kb.

Major histocompatibility complex (MHC) class I molecules are cell-surface glycoproteins that bind peptides and present them to T cells. The formation of a peptide-MHC complex is the initial step in specific, T cell-mediated immune responses. But, unlike other receptor-ligand systems, peptides are essential for a stable conformation of the MHC proteins. To investigate the contribution of every amino acid of octapeptides to the stability and antigenic integrity of MHC proteins, complex octapeptide libraries with one defined amino acid and mixtures of 19 amino acids in the remaining seven positions were synthesized and tested for their capacity to stabilize the conformation of the mouse MHC class I molecule H-2Kb. Peptide transporter-deficient RMA-S cells were employed in this study. Amino acid preferences found for the eight sequence positions reveal constitutional, volumetric, and steric constraints that govern peptide selection by MHC molecules. The pattern of amino acid preferences indicates that the peptides behave as integral parts of the MHC proteins and follow rules established for the interrelationship of primary sequence and the conformation and stability of proteins in general.

Amino Acid Sequence↗
PubMed1994

Distinct structural compartmentalization of the signal transducing functions of major histocompatibility complex class II (Ia) molecules.

Class II major histocompatibility complex encoded proteins (MHC class II or Ia molecules) are principal plasma membrane proteins involved in activation of both B and T cells during antigen-driven immune responses. Recent data indicate that class II molecules are more than simply recognition elements that provide a ligand for the T cell antigen receptor. Changes in B cell physiology that follow class II binding are now recognized as being required not only for the induction of T cell activation, but also for B cell activation and proliferation. It is interesting to note that class II molecules appear to transduce signals via two distinct mechanisms depending upon the differentiative state of the B cell on which they are expressed. While one of these pathways, involving cAMP generation and protein kinase C localization in the cytoskeletal/nuclear compartment, is seen in resting B cells, the second is seen in primed B cells and involves tyrosine kinase activation, inositol lipid hydrolysis, and Ca2+ mobilization. Use of this pathway is correlated with ability of class II to transduce signals leading to B cell proliferation. To begin to address the molecular basis of this unique, activation-dependent, differential coupling of class II to signaling pathways, we conducted mutational analysis of class II structural requirements for signal transduction. Here we report that the cytoplasmic (Cy) domains of I-Ak class II molecules are not required for either receptor-mediated activation of protein tyrosine phosphorylation or Ca2+ mobilization. This is in contrast to the requirement of the Cy domain of beta chain of class II for the alternate signaling pathway and efficient antigen presentation to autoreactive T cell lines. Disparate distribution of functional motifs within the MHC class II molecules may reflect use of distinct receptor associated effector molecules to sustain different modes of signal transduction in various class II-expressing cells.

Amino Acid Sequence↗
PubMed1996

The divergence of major histocompatibility complex class I genes in Sciurus aberti.

Major histocompatibility complex (MHC) class I genes encode cell surface molecules that bind and present immunogenic peptides to cytolytic T lymphocytes. We have developed a model using the MHC (Scab) of tassel-eared squirrels, Sciurus aberti, to investigate the evolution of MHC genes in subspecies that have been effectively isolated in comparable, if not identical, environments. Class I cDNAs from single S. aberti aberti and S. aberti kaibabensis squirrels were cloned and sequenced. These two cDNA transcripts differed by nucleotide substitutions that were predominantly located in codons impacting the peptide binding site, and nonsynonymous substitutions exceeded synonymous substitutions at these sites. These sequences also differed by the insertion of two amino acids in a beta-strand adjacent to position 45 in pocket B of the peptide binding site that may result in a deeper pocket with altered peptide specificity. This indel is present in additional Scab class I sequences, and class I sequences in five subspecies carry identically sized insertions. Phylogenetic analyses of exons 2, 3, and 4 with neighbor-joining and maximum parsimony methods depict that Scab class I sequences diverged at a point intermediate between murid class I sequences and class I sequences of primates, carnivores, and artiodactyls. The relative relatedness of Scab class I sequences to those in the latter group appears to be founded in relative similarities in exons 2 and 3, which encode the peptide binding site. These results bring into question the use of a single model for rodent class I sequences. Moreover, they demonstrate that the inclusion of exons 2 and 3 in phylogenetic analyses of class I may obscure true phylogenetic relationships, perhaps due to convergence through strong selective pressure.

Amino Acid Sequence↗
PubMed1990

Induction of tumour-specific immunity by manipulating the expression of major histocompatibility complex molecules on tumour cells.

Class I major histocompatibility complex (MHC) molecules form part of the target structure recognized by the host cytotoxic T cells (CTL) to reject tumour cells. Many types of malignant tumour cells are reported in which expression of class I MHC genes is down-regulated. By DNA-mediated gene transfer, it is possible to re-express the 'missing' syngeneic (genetically identical) or to introduce 'new' allogeneic (genetically dissimilar) class I MHC genes into these MHC-deficient tumours. In both instances, the immunogenicity of the transfected tumour cells is greatly enhanced and results in their rejection in vivo. More importantly, these 'modified' tumour cells, which are positive for class I MHC molecules, can simultaneously generate an immunity against the 'wild-type' tumour cells which do not express these molecules. These observations suggest the distinct possibility of using gene transfer as a molecular immunotherapeutic approach to abrogate tumour growth.

Animals↗
PubMed1995

Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains.

Reduction of major histocompatibility complex class I cell surface expression occurs in adenovirus-, herpes simplex virus-, human cytomegalovirus (HCMV)-, and murine cytomegalovirus-infected cell systems. Recently, it was demonstrated that the down-regulation mediated by HCMV infection is posttranslational, as a result of increased turnover of class I heavy chains in the endoplasmic reticulum (M. F. C. Beersma, M. J. E. Bijlmakers, and H. L. Ploegh, J. Immunol. 151:4455-4464, 1993; Y. Yamashita, K. Shimokata, S. Saga, S. Mizuno, T. Tsurumi, and Y. Nishiyama, J. Virol. 68:7933-7943, 1994. To identify HCMV genes involved in class I regulation, we screened our bank of HCMV deletion mutants for this phenotype. A mutant with a 9-kb deletion in the S component of the HCMV genome (including open reading frames IRS1 to US9 and US11) failed to down-regulate class I heavy chains. By examining the effects of smaller deletions within this portion of the HCMV genome, a 7-kb region containing at least nine open reading frames was shown to contain the genes required for reduction in heavy-chain expression. Furthermore, it was determined that at least two independent loci within the 7-kb region were able to cause class I heavy-chain down-regulation. One of these, US11, encodes a 32-kDa glycoprotein which causes down-regulation of class I heavy chains in the absence of other viral gene products. Hence, a specific function associated with a phenotype of the HCMV replicative cycle has been mapped to a dispensable gene region. These loci may be important for evasion of the host's immune response and viral persistence.

Astrocytoma↗
PubMed2000

Human immunodeficiency virus type 1 envelope epitope-specific CD4(+) T lymphocytes in simian/human immunodeficiency virus-infected and vaccinated rhesus monkeys detected using a peptide-major histocompatibility complex class II tetramer.

A tetrameric recombinant major histocompatibility complex (MHC) class II-peptide complex was used to quantitate human immunodeficiency virus type 1 (HIV-1) envelope (Env)-specific CD4(+) T cells in vaccinated and in simian/human immunodeficiency virus (SHIV)-infected rhesus monkeys. A rhesus monkey MHC class II DR molecule, Mamu-DR*W201, and an HIV-1 Env peptide (p46) were employed to construct this tetrameric complex. A p46-specific proliferative response was seen in sorted, tetramer-binding, but not nonbinding, CD4(+) T cells, directly demonstrating that this response was mediated by the epitope-specific lymphocytes. Although staining of whole blood from 10 SHIV-infected Mamu-DR*W201(+) rhesus monkeys failed to demonstrate tetramer-binding CD4(+) T cells (<0.02%), p46-stimulated peripheral blood mononuclear cells (PBMCs) from 9 of these 10 monkeys had detectable p46 tetramer-binding cells, comprising 0.5 to 15.2% of the CD4(+) T cells. p46-stimulated PBMCs from 7 of 10 Mamu-DR*W201(+) monkeys vaccinated with a recombinant canarypox virus-HIV-1 env construct also demonstrated p46 tetramer-binding cells, comprising 0.9 to 7.2% of the CD4(+) T cells. Thus, Env p46-specific CD4(+) T cells can be detected by tetrameric Mamu-DR*W201-p46 complex staining of PBMCs in both SHIV-infected and vaccinated rhesus monkeys. These epitope-specific cell populations appear to be present in peripheral blood at a very low frequency.

Animals↗