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At least 199 records · Page 11Linked to original sources
PubMed2005

Reconstitution of expression of H-2K region-encoded murine MHC class I glycoproteins in MHC class I-deficient B16BL6 melanoma cells affects the expression and function of antigen-processing machinery.

We have recently reported that reconstitution of expression of major histocompatibility complex (MHC) class I glycoproteins in MHC-deficient and highly metastatic B16BL6 melanoma cells attenuates their malignant capacities by modulation of compartmentalization and functions of cell membrane receptors for growth factors [Assa-Kunik E, et al. J Immunol 2003;171:2945-52]. Our present study provides evidence that re-expression of an H-2K MHC class I-encoding gene in these cells also augments the expression of the Tap-2 peptide transporter and the inducible proteasome subunits, i.e. Lmp-2, Lmp-7 and Lmp-10. Up-regulation of inducible proteasome subunits was also followed by a significant changed in the proteolytic activity of the proteasome complex. We suggest that, in addition to providing a framework for proper presentation of antigenic peptides, MHC class I glycoproteins may regulate the immune response by modulating the expression and function of other genes, whose products are essential for proper antigen processing and presentation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Generating MHC Class II+/Ii- phenotype after adenoviral delivery of both an expressible gene for MHC Class II inducer and an antisense Ii-RNA construct in tumor cells.

Tumor cells engineered by gene transduction to be MHC Class II+/Ii- are novel APCs capable of presenting endogenous tumor antigen epitopes to activate T helper cells. The MHC Class II+/Ii- tumor cell phenotype is created by transfecting genes for either CIITA or IFN-gamma, and inhibiting induced Ii mRNA by an Ii reverse gene construct (Ii-RGC). Adenoviral vectors are preferred for the delivery of such genes because of high infection efficiency and ubiquity of the adenoviral receptor on many cell types and tumors. Here we show that at 5 MOI (multiplicity of infection), recombinant adenoviruses with CIITA or IFN-gamma genes converted virtually all MC-38 colon adenocarcinoma cells and Renca renal carcinoma cells in culture to MHC Class II+/Ii+ cells. A single recombinant adenovirus with both genes for IFN-gamma and Ii-RGC (rAV/IFN-gamma/Ii-RGC) efficiently induced the MHC Class II+/Ii- phenotype. Injection of tumor nodules with rAV/Ii-RGC and rAV/CIITA/IFN-gamma combined with a suboptimal dose of rAV/IL-2 induced a potent antitumor immune response. The methods are adaptable for producing enhanced genetic vaccines, attenuated virus vaccines (eg, vaccinia), and ex vivo cell-based vaccines (dendritic and tumor cells).

Adenoviridae↗
PubMed1991

Expression of a class II major histocompatibility complex (MHC) heterodimer in a lipid-linked form with enhanced peptide/soluble MHC complex formation at low pH.

A murine class II major histocompatibility complex (MHC) heterodimer, Ek, expressed as a glycan-phosphatidyl inositol-anchored chimera on Chinese Hamster Ovary cells, can present peptides, but not processed antigen to T cells. This chimeric MHC requires a 100-times higher peptide concentration to achieve a two- to four-times lower level of T cell stimulation. Cleavage with phosphatidylinositol-specific phospholipase C and purification result in large quantities of heterodimer in a water-soluble form. Plates coated with this material and then incubated with peptide can efficiently stimulate the appropriate T cell hybridomas. This stimulation is significantly enhanced when peptides are preincubated with the plate-bound MHC molecules in a pH range (5.0-5.5) similar to that of late endosomes. More than half of the soluble Ek molecules can form a specific complex with cytochrome c peptides in this pH range. This suggests that class II MHC molecules undergo distinct conformational changes in endosomal compartments that render them more capable of forming functional complexes with peptide antigens, irrespective of other cell components.

Amino Acid Sequence↗
PubMed2006

Improving MHC binding peptide prediction by incorporating binding data of auxiliary MHC molecules.

MOTIVATION: Various computational methods have been proposed to tackle the problem of predicting the peptide binding ability for a specific MHC molecule. These methods are based on known binding peptide sequences. However, current available peptide databases do not have very abundant amounts of examples and are highly redundant. Existing studies show that MHC molecules can be classified into supertypes in terms of peptide-binding specificities. Therefore, we first give a method for reducing the redundancy in a given dataset based on information entropy, then present a novel approach for prediction by learning a predictive model from a dataset of binders for not only the molecule of interest but also for other MHC molecules. RESULTS: We experimented on the HLA-A family with the binding nonamers of A1 supertype (HLA-A*0101, A*2601, A*2902, A*3002), A2 supertype (A*0201, A*0202, A*0203, A*0206, A*6802), A3 supertype (A*0301, A*1101, A*3101, A*3301, A*6801) and A24 supertype (A*2301 and A*2402), whose data were collected from six publicly available peptide databases and two private sources. The results show that our approach significantly improves the prediction accuracy of peptides that bind a specific HLA molecule when we combine binding data of HLA molecules in the same supertype. Our approach can thus be used to help find new binders for MHC molecules.

Algorithms↗
PubMed1995

In vitro analysis of a primary, major histocompatibility complex (MHC)-restricted, cytotoxic T-lymphocyte response to avian leukosis virus (ALV), using target cells expressing MHC class I cDNA inserted into a recombinant ALV vector.

The interaction between the major histocompatibility complex (MHC) and cytotoxic T lymphocytes (CTLs) is an important component of the host's resistance to viral infections and tumor formation. In this study, an avian leukosis virus (ALV) vector system, RCASBP, expressing MHC chicken class I (B-F) cDNA was used to develop target cells expressing the chicken class I glycoproteins complexed with ALV antigens on the cell surface. Peripheral blood from chickens inoculated with ALV was shown to contain antigen-specific, MHC-restricted, CD8+ effector CTLs, using a 51Cr release assay utilizing the RCASBP B-F target cells. The stimulated effector cells were also predominantly alpha beta T-cell receptor-positive (TCR2) T cells. The CTL response varied between two haplotypes of chickens which differed in their response to Rous sarcoma virus (RSV)-induced tumors. Chickens with the B21 haplotype which regress RSV-induced tumors showed maximal cytolytic activity, while chickens with the B13 haplotype which do not regress RSV-induced tumors had minimal to no cytolytic activity. In addition to assessing the CTL response to ALV, the creation of MHC-specific immortal target cell lines will be extremely useful in evaluating CTL responses to other viral disease in chickens.

Animals↗
PubMed2005

MHC Class II-mediated apoptosis by a nonpolymorphic MHC Class II peptide proceeds by activation of protein kinase C.

It was demonstrated previously that a peptide derived from a conserved region of MHC class II, HLA-DQA1, inhibits proliferation of allogeneic T cells in vitro. Administration of HLA-DQA1 in conjunction with allogeneic cells at the time of priming or at the time of rechallenge prevented the development of the delayed type hypersensitivity response in vivo. The immunomodulatory effects of HLA-DQA1 were associated with the induction of apoptosis in B cells, macrophages, and dendritic cells via a caspase-independent pathway. This study investigated the binding site and mechanism that mediates cell death induced by HLA-DQA1. It was demonstrated that HLA-DQA1 binds to MHC class II on the cell surface, causing MHC class II signaling, initiation of protein kinase C signaling, and mitochondrial membrane depolarization with resultant apoptosis. The data indicate that HLA-DQA1 binds to MHC class II outside the groove, in a manner similar to superantigen. These results suggest that HLA-DQA1 is a novel immunotherapy that may provide an effective means of targeting professional antigen-presenting cells, in particular B cells.

Animals↗
PubMed1989

MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel.

The course of systemic infection with lymphocytic choriomeningitis virus was studied in mouse strains differing in the MHC or non-MHC background. Virus clearance rates differed significantly between H-2 identical strains as well as between congenic strains differing in the H-2L subregion, indicating that both H-2 and non-H-2 genes may influence the elimination of this virus. Differences in virus spread prior to appearance of the immune response could not explain the observed differences in clearance rate. On the other hand, inefficient clearance always correlated with low T cell responsiveness measured in terms of virus-specific cytotoxicity and delayed-type hypersensitivity, whereas no correlation was found with regard to NK cell activity and antiviral antibody response. Analysis of F1 progeny between H-2 identical high and low responder strains showed that low responsiveness with regard to all three parameters was recessive, indicating that natural tolerance is not the mechanism explaining non-MHC dependent low responsiveness in this system. The implications of these findings are discussed with specific reference to the role of MHC genes in controlling resistance to infectious diseases.

Animals↗
PubMed1992

Dissection of major histocompatibility complex (MHC) and T cell receptor contact residues in a Kb-restricted ovalbumin peptide and an assessment of the predictive power of MHC-binding motifs.

The effect of alanine substitution on the major histocompatibility complex (MHC) binding and T cell receptor recognition of the Kb-restricted ovalbumin 257-264 peptide was investigated. Positions 3, 5 and 8 of the octamer were important for Kb binding, as predicted from the motifs found in Kb-associated peptides, while mutations at positions 4, 6 and 7 affected cytotoxic T lymphocyte recognition. Substitutions at positions 1 and 2 had very minor effects on T cell recognition. In addition, we tested the capacity of sequence motifs to predict MHC binding by analysis of a series of peptides which all bear the minimal Kb motif. We found that possession of good motifs was not always sufficient to give strong MHC binding, indicating secondary effects of the residues flanking the "MHC anchor" positions.

Alanine↗
PubMed1996

Differential expression of CLIP:MHC class II and conventional endogenous peptide:MHC class II complexes by thymic epithelial cells and peripheral antigen-presenting cells.

Major histocompatibility complex (MHC) class II molecules expressed by thymic epithelial cells are involved in positive selection of CD4 T cells, whereas the high-avidity interaction of T cell receptors with the endogenous peptide: MHC class II complexes expressed on bone marrow (BM)-derived antigen-presenting cells (APC) and, to a lesser extent, on thymic epithelial cells mediate negative selection. To understand better the generation of the CD4 T cell repertoire both in the thymus and in the periphery we analyzed relative levels of expression of specific endogenous peptide: MHC class II complexes in thymic epithelial cells (TEC) and peripheral APC. Expression of E alpha52-68: I-A(b) and class II-associated invariant chain peptide (CLIP): I-A(b) complexes in thymic epithelial cells and in the bone-marrow derived splenic APC, i.e. B cells, was studied using YAe and 30-2 monoclonal antibodies which are specific for the corresponding complexes. To distinguish between expression of both complexes in radioresistant thymic epithelial elements and radiation sensitive BM-derived APC, radiation BM chimeras were constructed. Using immunohistochemical and immunochemical approaches we demonstrated that the level of expression of E alpha52-68: I-A(b) complexes in thymic epithelial cells is approximately 5-10% of that seen in splenic cells whereas total class II levels were comparable. In contrast, CLIP: I-A(b) complexes are expressed at substantially higher levels in TEC vs. splenic APC. This result demonstrates quantitative differences in expression of distinct peptide: MHC class II complexes in thymic epithelial cells and peripheral splenic APC.

Animals↗
PubMed2005

Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding.

Epitopes presented by major histocompatibility complex (MHC) class I molecules are selected by a multi-step process. Here we present the first computational prediction of this process based on in vitro experiments characterizing proteasomal cleavage, transport by the transporter associated with antigen processing (TAP) and MHC class I binding. Our novel prediction method for proteasomal cleavages outperforms existing methods when tested on in vitro cleavage data. The analysis of our predictions for a new dataset consisting of 390 endogenously processed MHC class I ligands from cells with known proteasome composition shows that the immunological advantage of switching from constitutive to immunoproteasomes is mainly to suppress the creation of peptides in the cytosol that TAP cannot transport. Furthermore, we show that proteasomes are unlikely to generate MHC class I ligands with a C-terminal lysine residue, suggesting processing of these ligands by a different protease that may be tripeptidyl-peptidase II (TPPII).

ATP-Binding Cassette Transporters↗
PubMed1986

Leukemia prevention and long-term survival of AKR mice transplanted with MHC-matched or MHC-mismatched bone marrow.

The current studies were designed to evaluate the effectiveness of marrow transplantation within and outside the major histocompatibility complex (MHC) on the long-term survival and occurrence of spontaneous leukemia in AKR mice. AKR mice, which were lethally irradiated and received MHC-matched marrow from CBA/J mice (CBA----AKR), never developed leukemia and were alive and remained healthy for up to 280 days post-transplant. These long-term surviving chimeras possessed substantial immune vigor when both cell-mediated and humoral responses were tested. Lethally irradiated AKR mice, which had received MHC-mismatched marrow (anti-Thy-1.2 treated or nontreated) from C57BL/6J mice (B6----AKR), never developed leukemia and survived up to 170 days post-transplant. However, both groups of these chimeras began dying 180 to 270 days post-transplant due to a disease process which could not be readily identified. Histological analysis of B6----AKR chimeras revealed severe lymphoid cell depletion in thymus and spleen; however, none of these chimeras exhibited classical features of acute graft versus host disease. Concanavalin A mitogenesis, primary antibody responses to sheep red blood cells and the production of interleukin 2 (IL-2) were suppressed in B6----AKR chimeras. IL-2 treatment of B6----AKR chimeras was shown to partially correct these deficiencies without stimulating mixed lymphocyte responsiveness to donor or host lymphocytes. These studies indicate that the use of MHC-mismatched marrow for the prevention of spontaneous AKR leukemia may rely on augmentative IL-2 therapy for complete immune reconstitution of leukemia-free chimeras.

AKR murine leukemia virus↗
PubMed2005

IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN.

IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins of the immune system (RPI) of human and other vertebrates. The NUMEROTATION concept of IMGT-ONTOLOGY has allowed to define a unique numbering for the variable domains (V-DOMAINs) and constant domains (C-DOMAINs) of the IG and TR, which has been extended to the V-LIKE-DOMAINs and C-LIKE-DOMAINs of the immunoglobulin superfamily (IgSF) proteins other than the IG and TR (Dev Comp Immunol 27:55--77, 2003; 29:185--203, 2005). In this paper, we describe the IMGT unique numbering for the groove domains (G-DOMAINs) of the MHC and for the G-LIKE-DOMAINs of the MHC superfamily (MhcSF) proteins other than MHC. This IMGT unique numbering leads, for the first time, to the standardized description of the mutations, allelic polymorphisms, two-dimensional (2D) representations and three-dimensional (3D) structures of the G-DOMAINs and G-LIKE-DOMAINs in any species, and therefore, is highly valuable for their comparative, structural, functional and evolutionary studies.

Amino Acid Sequence↗
PubMed2006

Macrophage MHC receptor 2: a novel receptor on allograft (H-2D(d)K(d))-induced macrophage (H-2D(b)K(b)) recognizing an MHC class I molecule, H-2K(d), in mice.

We previously reported that a population of allograft (H-2D(d)K(d))-induced macrophages (AIM) in C57BL/6 (H-2D(b)K(b)) mice exhibited major histocompatibility complex (MHC) haplotype (H-2D(d)) specific killing of the allograft (e.g., BALB/c skin and Meth A cells; H-2D(d)K(d)) in a macrophage MHC receptor (MMR)-dependent manner. In the present study, we isolated a cDNA clone encoding a novel receptor (MMR2) on AIM recognizing another MHC class I molecule, H-2K(d), by the expression cloning method using H-2K(d) tetramer and a monoclonal antibody (mAb; R12) specific for AIM. The cDNA (2359-bp) encoded a 677-amino acid polypeptide of a calculated molecular mass of 87 kDa and was found to be expressed exclusively on AIM among cells infiltrating into allografts on days 0-9 after transplantation. Confocal microscopy showed that HEK293T cells transfected with this cDNA were reactive toward the H-2K(d) molecule but not toward other MHC class I molecules such as H-2D(d), H-2D(b), H-2D(k), H-2K(b), H-2K(k), and H-2L(d) molecules. The binding of the H-2K(d) molecule to the transfectants was inhibited by the addition of R12 or anti-H-2K(d), but not by R15 (a mAb specific for H-2D(d) receptor) or anti-H-2D(d), mAb. Flow cytometric analysis revealed specific binding of H-2K(d) molecules to AIM (K(d)=2.7x10(-9) M); and the binding was completely suppressed by the addition of R12 mAb. These results demonstrate that a novel receptor (MMR2) for H-2K(d) molecules was induced on effector macrophages responsible for allograft (H-2D(d)K(d)) rejection by H-2D(b)K(b) mice.

Amino Acid Sequence↗
PubMed2002

Peptide-beta2-microglobulin-MHC fusion molecules bind antigen-specific T cells and can be used for multivalent MHC-Ig complexes.

Recombinant soluble MHC molecules are widely used for visualization, activation and inhibition of antigen-specific immune responses. Using a genetic approach, we have generated two novel peptide-beta2-microglobulin-MHC constructs. We have linked the MHC molecule with the peptide of interest, without limiting the recognition by the cognate TCR. This molecule can also be joined with the IgG heavy chain resulting in a dimeric MHC-Ig fusion protein. These molecules bind antigen-specific T cells with high specificity and sensitivity, therefore, providing a valuable tool for detection as well as enrichment of antigen-specific T cells.

Animals↗
PubMed1998

Spontaneous Borna disease in sheep and horses: immunophenotyping of inflammatory cells and detection of MHC-I and MHC-II antigen expression in Borna encephalitis lesions.

Borna disease (BD) has been recognized as a virally induced T-cell dependent immunopathological disorder of the central nervous system (CNS), as shown by experimental infection of rats with Borna disease virus (BDV). In contrast to the rat model, little is known about the pathogenesis of spontaneous BD in sheep and horses. The present study describes the brain lesions of 12 ovine and 11 equine cases of naturally occurring BD. A set of monoclonal and polyclonal antibodies was used in order to determine the cells operative in encephalitic lesions and to detect expression of MHC-I and MHC-II products in the brains of affected animals. In all cases investigated, a reaction pattern similar to that reported for the acute phase of BD in experimentally infected rats was noted. In brief, the majority of inflammatory cells in perivascular infiltrates (PVI) as well as parenchymal and meningeal infiltrates were CD3 +. CD4 + cells outnumbered CD8 + cells in PVI as well as in the parenchyma. Macrophages (defined by lysozyme immunoreactivity) were seen less often and B-cells or plasma cells (cells positive for lambda or kappa light chains) were demonstrated at lower numbers. TCR-1 + cells were found on very rare occasions in PVI of some sheep. MHC-I and MHC-II products were constantly expressed on inflammatory cells but inconsistently on astrocytes and neurons. Neuronal degeneration was not a major feature.

Animals↗
PubMed1992

Rat thymic epithelium positively selects mouse T cells with specificity for rat MHC class II antigens but fails to induce detectable tolerance in the mouse T cells to the rat MHC antigens.

BALB/c (H-2d) nude mice were grafted with allogeneic AKR/J (H-2k) or xenogeneic (ACI-N rat, RT1av1) fetal thymuses which were depleted of hemopoietic cells by incubating with 2'-deoxyguanosine (2'dGuo) in vitro prior to grafting. The nylon-wool-passed LN T cells from nude mice grafted with 2'dGuo-treated AKR/J thymus showed a poor proliferative response to B10BR (H-2k) stimulator cells, confirming that mouse thymic epithelium has the capacity to induce tolerance against the mouse MHC antigens on the thymic epithelium. On the other hand, the nylon-wool-passed LN T cells from nude mice grafted with untreated or 2'dGuo-treated ACI/N rat thymus showed significant proliferative responses to ACI/N, which can be blocked by anti-rat MHC class II mAb, whereas the nylon-wool-passed LN T cells from nude mice grafted with syngeneic thymus hardly responded to the xenogeneic stimulator cells. These results suggest that rat thymic stromal cells including thymic epithelium can not induce detectable tolerance in mouse T cells to rat MHC antigens; but rat thymic epithelium may positively select mouse T cells with specificity for rat MHC class II antigens, resulting in a mouse T cell repertoire with strong xeno-reactivity.

Animals↗
PubMed2002

Crystal structure of a SEA variant in complex with MHC class II reveals the ability of SEA to crosslink MHC molecules.

Although the biological properties of staphylococcal enterotoxin A (SEA) have been well characterized, structural insights into the interaction between SEA and major histocompatibilty complex (MHC) class II have only been obtained by modeling. Here, the crystal structure of the D227A variant of SEA in complex with human MHC class II has been determined by X-ray crystallography. SEA(D227A) exclusively binds with its N-terminal domain to the alpha chain of HLA-DR1. The ability of one SEA molecule to crosslink two MHC molecules was modeled. It shows that this SEA molecule cannot interact with the T cell receptor (TCR) while a second SEA molecule interacts with MHC. Because of its relatively low toxicity, the D227A variant of SEA is used in tumor therapy.

Amino Acid Sequence↗
PubMed2005

Two CD1 genes map to the chicken MHC, indicating that CD1 genes are ancient and likely to have been present in the primordial MHC.

CD1 molecules play an important role in the immune system, presenting lipid-containing antigens to T and NKT cells. CD1 genes have long been thought to be as ancient as MHC class I and II genes, based on various arguments, but thus far they have been described only in mammals. Here we describe two CD1 genes in chickens, demonstrating that the CD1 system was present in the last common ancestor of mammals and birds at least 300 million years ago. In phylogenetic analysis, these sequences cluster with CD1 sequences from other species but are not obviously like any particular CD1 isotype. Sequence analysis suggests that the expressed proteins bind hydrophobic molecules and are recycled through intracellular vesicles. RNA expression is strong in lymphoid tissues but weaker to undetectable in some nonlymphoid tissues. Flow cytometry confirms expression from one gene on B cells. Based on Southern blotting and cloning, only two such CD1 genes are detected, located approximately 800 nucleotides apart and in the same transcriptional orientation. The sequence of one gene is nearly identical in six chicken lines. By mapping with a backcross family, this gene could not be separated from the chicken MHC on chromosome 16. Mining the draft chicken genome sequence shows that chicken has only these two CD1 genes located approximately 50 kb from the classical class I genes. The unexpected location of these genes in the chicken MHC suggests the CD1 system was present in the primordial MHC and is thus approximately 600 million years old.

Amino Acid Sequence↗