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PubMed1994

Double labelling of major histocompatibility complex molecules and lysosomal protein lamp-1 on human dendritic cells.

In this study, double labelling for major histocompatibility complex (MHC) class I and class II molecules and for MHC molecules and the lysosomal membrane protein lamp-1 on ultrathin cryosections of dendritic cells isolated from human peripheral blood was performed. The plasma membrane proved to be positive for both MHC class I and MHC class II molecules and was labelled for only a very few lamp-1 molecules. MHC class I and MHC class II molecules did not co-localize intracellularly except in some peripherally located vesicles. However, many MHC class II-labelled vesicles were present in a juxtanuclear position but only some of them were co-labelled for lamp-1. These results indicate the presence of a separate, non-lysosomal compartment for class II molecules in dendritic cells.

Antigens, CD↗
PubMed1989

Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.

Major histocompatibility complex class I (MHC-I) expression on target cells is a prerequisite for antigen-specific T cell-mediated cytotoxicity (TCMC). Enhanced MHC-I expression has been attributed to interferons (IFNs) released from inflammatory cells. In previous studies, we found evidence of TCMC (invasion of non-necrotic muscle fibers by cytotoxic T cells) in polymyositis (PM) and in inclusion body myositis (IBM). We occasionally found evidence of TCMC in Duchenne dystrophy (DD) but not in dermatomyositis (DM). This study examines the relationships between TCMC, MHC-I expression, and IFN immunoreactivity in these diseases and normal controls. In controls, reactivity for MHC-I was confined to blood vessels. In all diseases, regenerating fibers expressed MHC-I. In IBM, PM and DD, all nonnecrotic muscle fibers invaded by CD8+ cells and some adjacent fibers expressed MHC-I. In DM, myriad muscle fibers expressed MHC-I but none were invaded by CD8+ cells. In all diseases, only a few mononuclear cells and no muscle fiber surfaces were immunoreactive for IFNs. We conclude that MHC-I expression on muscle fibers is necessary but not sufficient for TCMC in myopathy; that the biological significance of increased MHC-I expression in DM remains undefined; and that currently available and appropriately controlled immunocytochemical methods show no relationship between increased MHC-I expression on muscle fibers and local IFN synthesis by mononuclear cells.

Alkaline Phosphatase↗
PubMed1994

Human trophoblast interferons enhance major histocompatibility complex class I antigen expression on human term trophoblast cells in culture.

The expression and regulation of major histocompatibility complex class I (MHC class I) antigens by virus-induced human trophoblast interferons (tro-IFNs) were examined in term trophoblast cultures. Flow cytometry studies using fluorescence monoclonal antibodies against MHC class I antigens revealed that isolated cytotrophoblasts can express MHC class I antigens. The expression of these antigens increased with stimulation of trophoblast cultures with tro-IFN-alpha and -beta. One hundred IU tro-IFN-alpha and -beta/ml induced no significant higher levels of MHC class I antigens as compared with the control, whereas 1000 IU tro-IFN-alpha and -beta/ml did. The tro-IFN-enhanced expression of MHC class I antigens may be important as it increases the efficiency of local and viral antigen presentation, cytotoxicity by T cell response and local inflammatory processes, thereby preventing virus spread from mother to fetus.

Cells, Cultured↗
PubMed1991

Mouse hepatitis virus (MHV-4, JHM) blocks gamma-interferon-induced major histocompatibility complex class II antigen expression on murine cerebral endothelial cells.

The regulation of gamma-interferon-induced major histocompatibility complex (MHC) class II antigen expression on mouse cerebral endothelial cells by the neurotropic mouse hepatitis virus (MHV-4, JHM) was studied in vitro. The results presented demonstrate that MHV-4 can selectively block gamma-interferon-induced class II antigen expression on cerebral endothelial cells. The blocking effect of class II expression occurs in a strain-dependent manner, and is limited to virus-susceptible mouse strains. Virus replication is not required to obtain the blocking effect since UV-inactivated MHV-4 produces the same result. MHV-4 blocking of gamma-interferon-induced class II antigen expression is observed at both the cell surface (flow cytometry) and transcriptional level (Northern analysis).

Animals↗
PubMed1991

The effects of West Nile virus on major histocompatibility complex class I and II molecule expression by Lewis rat Schwann cells in vitro.

The expression of major histocompatibility complex (MHC) class I and II molecules by Lewis rat Schwann cells after infection with West Nile virus (WNV) in vitro was examined by fluorescence microscopy and flow cytometry. WNV enhanced the expression of MHC class I molecules and induced the expression of MHC class II molecules by Schwann cells. Irradiated medium from WNV-infected Schwann cell cultures upregulated class I molecule expression on dissociated Schwann cell cultures but did not induce the expression of class II molecules. This finding has implications for virally triggered autoimmune diseases of nervous tissue.

Animals↗
PubMed1987

The influence of major histocompatibility complex class I antigens on tumor growth and metastasis.

The work described here demonstrates the importance of major histocompatibility complex class I antigens for the control of tumor growth and metastasis by the host's immune system. In certain murine tumor cells which have lost expression of H-2 class I antigens, a de novo expression of H-2 can be achieved by transfection with syngeneic class I genes. In contrast to the parental cells the transfected tumors do not grow any more in syngeneic mice, or in other cases they do not form metastases. The studies suggest that the de novo expression of the H-2 antigens renders the tumors highly immunogenic and leads to effective recognition of a tumor-associated antigen in conjunction with the transfected H-2 antigen. These conclusions were confirmed in other tumor systems. For example, separation of a heterogeneous tumor into clones expressing high or low amounts of H-2 showed that only the tumor cell with low H-2 grew well in syngeneic mice, whereas the H-2 high tumor clones were rejected. In other studies in vitro induction by IFN-gamma of H-2 antigen on H-2 negative tumors led to reduced tumor growth in vivo which was due to the increased immunogenicity. About 10% of human tumors are also low or defective for HLA class I expression and often these tumors appear to be more malignant. The class I negative tumors could either have arisen from class I low or negative tissues or are HLA loss variants which escaped the attack of the immune system. Altogether, our studies and the data of other laboratories demonstrate the important role of class I antigens for anti-tumor immunity and they suggest that modulation of class I expression by gene transfection or by induction with soluble mediators could be a useful tool for the manipulation of tumor immunity.

Animals↗
PubMed1989

An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis.

The class II region of the human major histocompatibility complex in seven common HLA haplotypes has been analyzed using pulsed-field gel electrophoresis, restriction enzymes that cut genomic DNA infrequently, and Southern blotting. This analysis has revealed that there are differences in the amount of DNA present in the DQ and DR subregions dependent on the haplotype. The class II region of the DR3 haplotype spans approximately 750 kb and has the same amount of DNA as the class II region of the DR5 and DR6 haplotypes. However, the DR2 haplotype has approximately 30 kb more DNA within the DR subregion. The DR4 haplotype has an additional approximately 110 kb of DNA within the DQ or DR subregions compared to the DR3, DR5, and DR6 haplotypes. These haplotype-specific differences could have some bearing both on the analysis of disease susceptibility and on the ability of chromosomes possessing different HLA haplotypes to recombine within the DQ/DR subregions.

Blotting, Southern↗
PubMed1987

Analysis of major histocompatibility complex class I gene transcription using oligonucleotide probes.

Many highly homologous genes are present in the murine major histocompatibility complex (MHC) class I gene family. Consequently, it is difficult to distinguish between RNA transcripts of individual class I genes solely on the basis of nucleic acid hybridization analysis using DNA probes over 50 base pairs long. To avoid this problem, I have designed and synthesized a set of oligonucleotide probes capable of detecting transcripts of single class I genes in the MHC of C57BL/10 mice or sets of allelic class I genes at the same genetic locus in MHC disparate mouse strains. Using these probes, it is possible to determine the relative abundance of specific class I gene transcripts in a wide variety of cell and tissue types from inbred or MHC disparate mice. Examples of the use of these probes to detect different class I gene transcripts in cloned murine T cells, T cells transformed with Radiation Leukemia Virus, chemically induced thymoma cell lines and embryonic tissues are described. The results of these experiments are discussed in the light of possible roles of class I antigens in tumorigenesis or in early development.

Animals↗
PubMed2006

Structural basis for a major histocompatibility complex class Ib-restricted T cell response.

In contrast to antigen-specific immunity orchestrated by major histocompatibility complex (MHC) class Ia molecules, the ancestrally related nonclassical MHC class Ib molecules generally mediate innate immune responses. Here we have demonstrated the structural basis by which the MHC class Ib molecule HLA-E mediates an adaptive MHC-restricted cytotoxic T lymphocyte response to human cytomegalovirus. Highly constrained by host genetics, the response showed notable fine specificity for position 8 of the viral peptide, which is the sole discriminator of self versus nonself. Despite the evolutionary divergence of MHC class Ia and class Ib molecules, the structure of the T cell receptor-MHC class Ib complex was very similar to that of conventional T cell receptor-MHC class Ia complexes. These results emphasize the evolutionary 'ambiguity' of HLA-E, which not only interacts with innate immune receptors but also has the functional capacity to mediate virus-specific cytotoxic T lymphocyte responses during adaptive immunity.

Animals↗
PubMed2003

Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain.

Dendritic cells (DCs) can present extracellularly derived antigens in the context of major histocompatibility complex (MHC) class I molecules, a process called cross-presentation. Although recognized to be important for priming of T cell responses to many viral, bacterial and tumor antigens, the mechanistic details of this alternative antigen-presentation pathway are poorly understood. We demonstrate here the existence of an endolysosomal compartment in DCs where exogenously derived peptides can be acquired for presentation to T cells, and show that the MHC class I cytoplasmic domain contains a tyrosine-based targeting signal required for routing MHC class I molecules through these compartments. We also report that transgenic mice expressing H-2K(b) with a tyrosine mutation mount inferior H-2K(b)-restricted cytotoxic T lymphocyte responses against two immunodominant viral epitopes, providing evidence of a crucial function for cross-priming in antiviral immunity.

Animals↗
PubMedDate not supplied

Temporal and regional regulation of major histocompatibility complex class I expression at the bovine uterine/placental interface.

In most mammals trophoblast cells do not express major histocompatibility complex (MHC) antigens. This probably protects the placenta from immune attack. We have used immunohistochemistry to study the ontogeny of MHC class I expression by bovine trophoblast and endometrial epithelial cells. The interplacentomal, placentomal arcade and placentomal villous/crypt regions were studied. In the interplacentomal region a substantial proportion of trophoblast cells were class I positive from the sixth month on and about half of the endometrial epithelium was class I positive throughout pregnancy. In the arcade region trophoblast class I expression was first observed in the sixth month, increased slowly and peaked at term. Here there was no endometrial epithelial class I expression until term and then only a small percentage of cells were positive. In contrast, in the placentomal villous/crypt region both trophoblast and endometrial epithelium were class I negative throughout gestation. This study shows that cattle have extensive trophoblast class I expression. Moreover class I expression on placentomal, cryptal endometrial epithelium is shut down. Because binucleate trophoblast cells migrate and fuse with endometrial epithelial cells, total shut down of class I expression in areas of intimate interdigitation may be critical for avoidance of immunological rejection.

Animals↗
PubMed1989

Expression of major histocompatibility complex class I antigens in rat muscle cultures: the possible developmental role in myogenesis.

The expression of major histocompatibility complex class I antigens was demonstrated on aneurally cultured rat muscle cells. Myoblasts showed constitutive expression of class I antigens on their cell surfaces. The presence of the antigens was transitory, disappearing as myoblasts fused and differentiated into multinucleate myotubes. Furthermore, antibody against rat class I antigens showed an inhibitory effect on the generation of myotubes during muscle development. Although mature myotubes did not show any detectable levels of class I antigens on their cell surface, soluble factors from concanavalin A-activated spleen cells or interferon gamma could induce the expression of class I antigens on muscle fibers. These results suggest that the expression of class I antigens on muscle cells is not only immunologically modulated but also developmentally regulated and that the antigens may play a role in cell recognition and interactions during the fusion process of myogenesis.

Animals↗
PubMed1989

Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

To study the mechanism of maintenance of polymorphism at major histocompatibility complex (MHC) loci, synonymous and nonsynonymous (amino acid-altering) nucleotide substitutions in the putative antigen-recognition site (included in the first domain of the MHC molecule) and other regions of human and mouse class II genes were examined. In the putative antigen-recognition site, the rate of nonsynonymous substitution was found to exceed that of synonymous substitution, whereas in the second domain the former was significantly lower than the latter. In light of a previous theoretical study and parallel findings in class I MHC loci, we conclude that the unusually high degree of polymorphism at class II MHC loci is caused mainly by overdominant selection (heterozygote advantage) operating in the antigen-recognition site.

Alleles↗
PubMed1994

Regulation of receptor internalization by the major histocompatibility complex class I molecule.

We showed previously that peptides derived from the alpha 1 domain of the major histocompatibility complex class I protein (MHC-I) inhibit internalization of some receptors, thereby increasing the steady-state number of active receptors on the cell surface. In consequence, sensitivity to hormone (e.g., insulin) is enhanced, transport (e.g., of glucose by GLUT-4) is increased, and carrier proteins (e.g., transferrin) operate less efficiently. Now we report that a bioactive peptide (but not closely related inactive ones) binds to MHC-I on the cell surface, not in the groove but apparently to the alpha 1 helix. The binding is saturable, and the number of peptide binding sites on the cell surface approximately equals the number of MHC-I molecules. Antibodies to MHC-I inhibit peptide binding. Most significant, antibodies to MHC-I mimic the effect of a bioactive peptide, inhibiting receptor internalization. These results indicate that MHC-I participates in the regulation of cell surface receptor activity.

Amino Acid Sequence↗
PubMed1996

beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism.

Hemochromatosis (HC) is an inherited disorder of iron absorption, mapping within the human major histocompatibility complex (MHC). We have identified a multigene system in the murine MHC that contains excellent candidates for the murine equivalent of the human HC locus and implicate nonclassical class I genes in the control of iron absorption. This gene system is characterized by multiple copies of two head-to-head genes encoded on opposite strands and driven by one common regulatory motif. This regulatory motif has a striking homology to the promoter region of the beta-globin gene, a gene obviously involved in iron metabolism and hence termed beta-globin analogous promoter (betaGAP). Upstream of the betaGAP sequence are nonclassical class I genes. At least one of these nonclassical class I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron absorption. Also expressed in the gastrointestinal tract and downstream of the betaGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based on these observations, we hypothesized that the genes that seem to be controlled by the betaGAP regulatory motifs would be responsible for the control of Fe absorption. As a test of this hypothesis, we predicted that mice which have altered expression of class I gene products, the beta2-microglobulin knockout mice, [beta2m(-/-)], would develop Fe overload. This prediction was confirmed, and these results indicate beta2m-associated proteins are involved in the control of intestinal Fe absorption.

Animals↗
PubMed1998

Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects.

Protective/suppressive major histocompatibility complex (MHC) class II alleles have been identified in humans and mice where they exert a disease-protective and immunosuppressive effect. Various modes of action have been proposed, among them differential expression of MHC class II genes in different types of antigen-presenting cells impacting on the T helper type 1 (Th1)-Th2 balance. To test this possibility, the expression of H-2 molecules from the four haplotypes H-2(b), H-2(d), H-2(k), and H-2(q) was determined on bone marrow-derived macrophages (BMDMs) and splenic B cells. The I-Ab and I-Ek molecules, both well characterized as protective/suppressive, are expressed at a high level on almost all CD11b+ BMDMs for 5-8 days, after which expression slowly declines. In contrast, I-Ad, I-Ak, and I-Aq expression is lower, peaks over a shorter period, and declines more rapidly. No differential expression could be detected on B cells. In addition, the differential MHC class II expression found on macrophages skews the cytokine response of T cells as shown by an in vitro restimulation assay with BMDMs as antigen-presenting cells. The results indicate that macrophages of the protective/suppressive haplotypes express MHC class II molecules at a high level and exert Th1 bias, whereas low-level expression favors a Th2 response. We suggest that the extent of expression of the class II gene gates the back signal from T cells and in this way controls the activity of macrophages. This effect mediated by polymorphic nonexon segments of MHC class II genes may play a role in determining disease susceptibility in humans and mice.

Animals↗
PubMed2001

Major histocompatibility complex class I molecules bind natural peptide ligands lacking the amino-terminal binding residue in vivo.

Major histocompatibility complex (MHC) class I-peptide complexes are stabilized by multiple interactions, including those of the peptidic NH(2)-terminal group in the A pocket of the MHC molecule. In this study, the characterization of four natural HLA-B39 ligands lacking the amino-terminal binding residue is reported. These peptides were found in the endogenous peptide pool of one or more of the B*3901, B*3905, and B*3909 allotypes and sequenced by nanoelectrospray mass spectrometry. Control experiments ruled out that they resulted from exopeptidase trimming of their NH(2)-terminally extended counterparts: NAc-SHVAVENAL, EHGPNPIL, IHEPEPHIL, and EHAGVISVL, also present in the same peptide pools, during purification. HAGVISVL and HVAVENAL behaved similarly to the corresponding NH(2)-terminally extended peptides in their binding to B*3901 and B*3909 at the cell surface in vitro, and in cell surface stabilization of B*3901. This is, to our knowledge, the first demonstration that peptides lacking the amino-terminal binding residue bind in vivo to classical MHC class I molecules. The results indicate that canonical MHC-peptide interactions in the A pocket are not always necessary for endogenous peptide presentation.

Amino Acid Sequence↗
PubMed1993

Polymorphisms in pockets of major histocompatibility complex class I molecules influence peptide preference.

The set of peptides that is bound by a given major histocompatibility complex class I product can be described by one or two properly spaced anchor residues, and two properly spaced peptide termini, approximately 8-10 residues apart. Using radiolabeled peptide libraries, we examined whether mutations in those "pockets" in class I Kb molecules that do not seem critically involved in the interaction with the peptide anchor residues, do exert an effect on the set of preferred peptides. We find that mutations in all the pockets found in the structure of Kb have a significant effect on the peptide preference of the molecule, and their recognition by cytotoxic T cells. Alterations in substrate specificity are also observed for mutations involving residues that interact with main chain atoms in both peptide termini. These findings challenge a static view of the interaction of peptide termini with their respective pockets in the class I molecule, and imply a role for the minor pockets in peptide selectivity.

Amino Acid Sequence↗