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PubMed1993

Mice lacking major histocompatibility complex class I and class II molecules.

Mice lacking major histocompatibility complex (MHC) antigens were generated by mating beta 2-microglobulin-deficient, and therefore class I-deficient, animals with MHC class II-deficient animals. When housed under sterile conditions, the resulting MHC-deficient mice appear healthy, survive for many months, and breed successfully. Phenotypically, MHC-deficient mice are depleted of CD4+ and CD8+ T cells in peripheral lymphoid organs due to a lack of appropriate restricting elements. In contrast, the B-cell compartment of these animals appears intact, and MHC-deficient mice can mount specific antibody responses when challenged with a T-independent antigen. Spleen cells from MHC-deficient animals are poor stimulators and responders in a mixed lymphocyte reaction. Despite their relatively weak cellular immune responses in vitro, MHC-deficient mice reject allogeneic skin grafts with little delay, and grafts from MHC-deficient animals are rapidly rejected by normal allogeneic recipients. Taken together, these results emphasize the plasticity of the immune system and suggest that MHC-deficient mice may be useful for examining compensatory mechanisms in severely immunocompromised animals.

Animals↗
PubMed1995

Binding of an invariant-chain peptide, CLIP, to I-A major histocompatibility complex class II molecules.

Invariant chain (Ii) associates with major histocompatibility complex (MHC) class II molecules and is crucial for antigen presentation by class II molecules. The exact nature of Ii interaction with MHC class II molecules remains undefined. A nested set of Ii peptides, CLIPs (class II-associated Ii peptides), have been eluted from various MHC class II molecules, suggesting that CLIPs correspond, at least in part, to the Ii motif which blocks the conventional peptide binding site in MHC class II molecules. Here we report how CLIPs interact with class II MHC molecules, I-A. We have identified regions critical for binding of CLIPs and I-A class II molecules. In most cases, the binding of CLIPs to a number of I-A molecules is modulated by the steric bulk of methionine residues at positions 93 and 99. In addition, the binding of CLIPs to an I-A molecule, I-Au, is sensitive to substitutions at aspartic acid-59 in the alpha chain and threonine-86 in the beta chain, whereas the binding of an antigen-derived peptide is not. Taken together, these results provide an insight as to how CLIPs bind to MHC class II heterodimers.

Animals↗
PubMed1996

Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.

Animals↗
PubMed1998

Diversification, expression, and gamma delta T cell recognition of evolutionarily distant members of the MIC family of major histocompatibility complex class I-related molecules.

Distant relatives of major histocompatibility complex (MHC) class I molecules, human MICA and MICB, function as stress-induced antigens that are broadly recognized by intestinal epithelial gamma delta T cells. They may thus play a central role in the immune surveillance of damaged, infected, or otherwise stressed intestinal epithelial cells. However, the generality of this system in evolution and the mode of recognition of MICA and MICB are undefined. Analysis of cDNA sequences from various primate species defined translation products that are homologous to MICA and MICB. All of the MIC polypeptides have common characteristics, although they are extraordinarily diverse. The most notable alterations are several deletions and frequent amino acid substitutions in the putative alpha-helical regions of the alpha1 alpha2 domains. However, the primate MIC molecules were expressed on the surfaces of normal and transfected cells. Moreover, despite their sharing of relatively few identical amino acids in potentially accessible regions of their alpha1 alpha2 domains, they were recognized by diverse human intestinal epithelial gamma delta T cells that are restricted by MICA and MICB. Thus, MIC molecules represent a family of MHC proteins that are structurally diverse yet appear to be functionally conserved. The promiscuous mode of gamma delta T cell recognition of these antigens may be explained by their sharing of a single conserved interaction site.

Amino Acid Sequence↗
PubMed1995

Association of the invariant chain with major histocompatibility complex class I molecules directs trafficking to endocytic compartments.

Major histocompatibility complex (MHC) class I and class II molecules have been shown to present peptides of different origin to alpha beta T cells. Most peptides presented by class I molecules are derived from endogenously synthesized proteins, whereas most peptides presented by class II molecules are from exogenous sources. This functional dichotomy can largely be achieved by the preferential intracellular association of the invariant chain (Ii) with MHC class II molecules, which may inhibit binding of endogenous peptides to class II molecules and direct them to endocytic compartments where extracellularly derived peptides can be sampled. Here, we show that Ii also can associate with a subset of MHC class I molecules and direct them to endocytic compartments. Ii was coprecipitated with class I molecules after lysis of human lymphocytes in mild detergent such as 3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonic acid or digitonin, and the association was more clearly visualized by the use of dithiobis[succinimidyl-propionate], a homobifunctional chemical cross-linker. The class I.Ii complex was reconstituted in Ii negative cells by transfection of corresponding cDNA clones and was found to be transported through the Golgi to acidic endocytic compartments. These observations may explain how some exogenous antigens can be presented by MHC class I molecules and how MHC class II molecules can bind self peptides derived from MHC class I molecules in endocytic compartments.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1999

Functional early endosomes are required for maturation of major histocompatibility complex class II molecules in human B lymphoblastoid cells.

Major histocompatibility complex (MHC) class II molecules are targeted together with their invariant chain (Ii) chaperone from the secretory pathway to the endocytic pathway. Within the endosome/lysosome system, Ii must be degraded to enable peptide capture by MHC class II molecules. It remains controversial exactly which route or routes MHC class II/Ii complexes take to reach the sites of Ii processing and peptide loading. We have asked whether early endosomes are required for successful maturation of MHC class II molecules by using an in situ peroxidase/diaminobenzidine compartment ablation technique. Cells whose early endosomes were selectively ablated using transferrin-horseradish peroxidase conjugates fail to mature their newly synthesized MHC class II molecules. We show that whereas transport of secretory Ig through the secretory pathway is virtually normal in the ablated cells, newly synthesized MHC class II/Ii complexes never reach compartments capable of processing Ii. These results strongly suggest that the transport of the bulk of newly synthesized MHC class II molecules through early endosomes is obligatory and that direct input into later endosomes/lysosomes does not take place.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2000

Determinants of the peptide-induced conformational change in the human class II major histocompatibility complex protein HLA-DR1.

The human class II major histocompatibility complex protein HLA-DR1 has been shown previously to undergo a distinct conformational change from an open to a compact form upon binding peptide. To investigate the role of peptide in triggering the conformational change, the minimal requirements for inducing the compact conformation were determined. Peptides as short as two and four residues, which occupy only a small fraction of the peptide-binding cleft, were able to induce the conformational change. A mutant HLA-DR1 protein with a substitution in the beta subunit designed to fill the P1 pocket from within the protein (Gly(86) to Tyr) adopted to a large extent the compact, peptide-bound conformation. Interactions important in stabilizing the compact conformation are shown to be distinct from those responsible for high affinity binding or for stabilization of the complex against thermal denaturation. The results suggest that occupancy of the P1 pocket is responsible for partial conversion to the compact form but that both side chain and main chain interactions contribute to the full conformational change. The implications of the conformational change to intracellular antigen loading and presentation are discussed.

Amino Acid Sequence↗
PubMed2000

Peptide specificity of RT1-A1(c), an inhibitory rat major histocompatibility complex class I natural killer cell ligand.

The rat major histocompatibility complex class Ia allelomorph RT1-A1(c) is a potent ligand for the recently identified inhibitory rLy-49 receptor, STOK-2. With the ultimate objective of studying the interactions of these molecules using structural and functional methods, we undertook a detailed study of its peptide specificity. The study revealed that designing an "ideal peptide" by choosing the most abundant residues in the "binding motif" obtained by pool sequencing does not necessarily yield an optimal binding peptide. For RT1-A1(c), as many as four positions, P2, P4, P5, and P9, were detected as putative anchors. Since this molecule displays a preference for highly hydrophobic peptides, we tested binding of peptides derived from the known leader peptide sequences of other rat histocompatibility complex class I molecules. One such peptide, found to bind well, requiring 1.6 microm peptide to achieve 50% stabilization, was searched for in vivo. Natural RT1-A1(c) binding peptides were purified from rat splenocytes and characterized by mass spectrometry using a combined matrix-assisted laser desorption ionization/time-of-flight and quadrupole time-of-flight approach. Results showed that the signal sequence-derived peptide was not detectable in the purified peptide pool, which was composed of a complex spectrum of peptides. Seven of these self-peptides were successfully sequenced.

Animals↗
PubMed1999

Presentation of cytosolic glycosylated peptides by human class I major histocompatibility complex molecules in vivo.

Antigens presented by class I major histocompatibility complex (MHC) molecules for recognition by cytotoxic T lymphocytes consist of 8-10-amino-acid-long cytosolic peptides. It is not known whether posttranslationally modified peptides are also presented by class I MHC molecules in vivo. Many different posttranslational modifications occur on cytoplasmic proteins, including a cytosolic O-beta-linked glycosylation of serine and threonine residues with N-acetylglucosamine (GlcNAc). Using synthetic glycopeptides carrying the monosaccharide O-beta-GlcNAc substitution on serine residues, we have shown that glycopeptides bind efficiently to class I MHC molecules and elicit a glycopeptide-specific cytotoxic T lymphocyte response in mice. In this study, we provide evidence that peptides presented by human class I MHC molecules in vivo encompass a small, significant amount of glycopeptides, constituting up to 0.1% of total peptide. Furthermore, we find that carbohydrate structures present on glycopeptides isolated from class I MHC molecules are dominated by the cytosolic O-beta-GlcNAc substitution, and synthetic peptides carrying this substitution are efficiently transported by TAP (transporter associated with antigen presentation) into the endoplasmic reticulum. Thus, in addition to unmodified peptides, posttranslationally modified cytosolic peptides carrying O-beta-linked GlcNAc can be presented by class I MHC molecules to the immune system.

ATP-Binding Cassette Transporters↗
PubMed1999

Differential regulation of constitutive major histocompatibility complex class I expression in T and B lymphocytes.

Major histocompatibility complex (MHC) class I antigens are constitutively expressed yet highly induced by interferon (IFN) during inflammation. We found that not only IFN-induced but also normal basal expression of MHC I required IFN receptors and signal transducer and activator of transcription (STAT)1, providing genetic evidence for continuous IFN signaling. Surprisingly, an IFN-independent requirement for STAT1 was also found, specifically in T lymphocytes, where MHC class I expression was not fully accounted for by IFN signaling. This IFN-independent pathway maintained tyrosine phosphorylation of STAT1 in T but not B lymphocytes even in the absence of IFN receptors. Interestingly, interleukin (IL)-7 selectively activated STAT1 and induced MHC class I in mature T but not B cells. These loss of function studies demonstrate an essential role of endogenous IFN and activated STAT1 for constitutive MHC class I expression in normal mice and define IL-7-dependent but IFN-independent regulation of STAT1 restricted to T lymphocytes.

Animals↗
PubMed2000

The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules.

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive ("allorestricted") T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.

Animals↗
PubMed1991

DNase I hypersensitive sites flank the mouse class II major histocompatibility complex during B cell development.

The mouse class II major histocompatibility complex (MHC) encodes a polymorphic, multigene family important in the immune response, and is expressed mainly on mature B cells, on certain types of dendritic cells and is also inducible by gamma-interferon on antigen presenting cells. To study the regulatory elements which control this expression pattern, we have examined the chromatin structure flanking the class II MHC region, in particular during B cell differentiation. Using a panel of well-characterised mouse cell lines specific for different stages of B cell development (pre-B, B, plasma cell) as well as non-B cell lines, we have mapped the DNase I hypersensitive (DHS) sites adjacent to the mouse MHC class II region. The results presented show, for the first time that there are specific hypersensitive sites flanking the class II MHC locus during pre B cell, B cell and plasma cell stages of B cell differentiation, irrespective of the status of class II MHC expression. These hypersensitive sites are not found in T cell, fibroblast or uninduced myelomonocytic cell lines. This suggests that these DHS sites define a developmentally stable, chromatin structure, which can be used as a marker of B cell lineage commitment and may indicate that a combination of these hypersensitive sites reflect regulatory proteins involved in the immediate expression of a particular class II MHC gene or possibly control of the entire locus.

Animals↗
PubMed1997

Bovine luteal cells elicit major histocompatibility complex class II-dependent T-cell proliferation.

Major histocompatibility complex (MHC) class II molecules are expressed in the bovine corpus luteum (CL) in a manner correlating with luteolysis. Whether bovine luteal cells can stimulate T-cell proliferation in a class II-restricted manner was investigated. Staphylococcal enterotoxin B (SEB) enhances T-cell proliferation by a mechanism requiring MHC class II molecules and was used to examine stimulation of T-cell proliferation by luteal cells. Luteal cells from midcycle or regressing CL (induced by prostaglandin F2 alpha) were cocultured with autologous T cells in the presence of no treatment, SEB (1 microgram/ml), or SEB + anti-MHC class II antibody (3 micrograms/ml); and proliferation was assessed by incorporation of tritiated thymidine. T cells proliferated in the presence of cells from regressing CL more than when in the presence of midcycle cells (118,309 +/- 20,567 vs. 75,261 +/- 12,494 cpm; p < 0.05). Anti-MHC attenuated this response of cells from regressing CL (81,108 cpm +/- 13,249; p < 0.05). Without SEB, T cells proliferated when cultured with cells from regressing, but not midcycle, CL (4637 +/- 816 vs. 2117 +/- 589 cpm; p < 0.03). These results suggest that luteal cells can function as antigen-presenting cells in vitro and that prostaglandin F2 alpha may enhance their ability to present antigen.

Animals↗
PubMed1988

Lack of correlation between the induction of donor class I and class II major histocompatibility complex antigens and graft rejection.

The induction of donor major histocompatibility complex (MHC) antigens on nonrejected and rejected rat renal allografts was compared at various times after transplantation in two strain combinations, DA-to-PVG and LEW-to-DA. Graft rejection was prevented by preoperative donor-specific blood transfusion (DST). Quantitative absorption analysis and immunohistology were performed using monoclonal antibodies specific for donor class I and class II MHC antigens. A significant increase in the expression of donor MHC antigens, both class I and class II, was demonstrated on nonrejected as well as rejected kidneys after transplantation. A kinetic analysis showed that induction of donor class I antigens was accelerated on the nonrejected grafts, and by day 5 the nonrejected kidneys showed increased expression of class I antigen when compared with the rejected grafts (a 37- vs. a 25-fold increase in expression). Increased expression of donor class I antigens persisted on the nonrejected grafts and was still detectable on long-term-surviving kidneys, 50 days after transplantation. The magnitude of class II antigen induction was similar on both rejected and nonrejected grafts (8-fold by 5 days after transplantation). Immunohistology demonstrated that class I and class II antigens were induced on identical structures in the kidney in both situations. In particular the vessel endothelia, which do not express class II antigens in normal kidney, become strongly positive in both rejected and nonrejected grafts 5 days after transplantation. Although renal allograft rejection is completely suppressed in rats given a single donor-specific blood transfusion before transplantation, graft survival cannot be explained by the lack of induction of donor MHC antigens. Donor MHC antigens are induced on these nonrejected kidney grafts, and therefore they could act as target molecules for the effector cells that mediate graft destruction. Thus the induction of donor MHC antigens on tissue allografts should not be considered as indicative of a rejection response resulting in graft destruction.

Animals↗
PubMed1988

The killing of tumour cell targets coupled to tuberculin (PPD) by human and murine PPD-reactive T helper clones. II. Major histocompatibility complex restriction of killing.

This paper takes up the major histocompatibility complex (MHC) restriction of killing by a murine and a human tuberculin (PPD)-specific T helper clone of PPD-Con A bound targets. In the previous paper we demonstrated that the specificity of killing of such targets was directed against PPD and not the lectin. This paper provides further evidence to suggest that the PPD-specific clones recognize PPD on PPD-Con A-bound cells though the T cell antigen receptor complex, since the killing was restricted by MHC class II products. Using a range of syngeneic, allogeneic, and semi-syngeneic targets we have shown the fine specificity of the restricting element to be one of the two alleles of the DR region (DR 2) for the human clone, and to be the I-A subregion for the murine clone. Binding studies with radiolabelled class II antibodies were performed to see whether killing efficiency was dependent on the number of class II products expressed. The findings showed that the human B-EBV targets express 2-3 x 10(6) molecules per cell, while the susceptible murine tumours, the Abelson line and the 6A tumour, only expressed 600-800 binding sites per cell. Target cell susceptibility appeared to be linked to the number of class II molecules expressed; thus the syngeneic murine MBL-2 tumour expressing 200-300 binding sites per cell was not killed and the lysis of the 6A and Abelson tumours could be enhanced by doubling the number of class II binding sites by incubating cells with Con A-conditioned medium. However, maximum lysis did not exceed 30-40%, suggesting that class II expression alone did not govern killing.

Animals↗
PubMed1996

Linkage disequilibrium between HLA class II (DR, DQ, DP) and antigen processing (LMP, TAP, DM) genes of the major histocompatibility complex.

TAP, LMP and DM genes map within the major histocompatibility complex (MHC) class II region between the DQB1 and DPB1 loci, and are involved in the processing of peptides bound to HLA class I or class II molecules. In order to determine the various linkage disequilibria existing between these genes and HLA class II genes, we have analyzed TAP1, TAP2, LMP2, DMA, DMB, DRB1, DQA1, DQB1 and DPB1 polymorphisms in 162 unrelated healthy Caucasian individuals. Many positive or negative associations were observed between alleles at these loci, such as between DR/DQ and TAP2, DM or LMP, between DP and DMB, and between TAP2 and DM, TAP2 and LMP. Conversely, no linkage disequilibrium was detected between some closely related genes (DR/DQ and TAP1, TAP1 and TAP2, LMP2 and DM), in agreement with the existence of recombination hot spots in this region. Other weak linkage disequilibria are likely to exist in this region. These data allow to define some conserved MHC class II haplotypes including HLA class II and TAP, LMP and DM alleles. Furthermore, the knowledge of such linkage disequilibria is of outstanding importance in order to avoid misinterpretation of the data when studying MHC class II associations with autoimmune diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Altered expression of major histocompatibility complex (MHC) antigens by epidermal tumours.

Alteration in the major histocompatibility complex (MHC) antigen expression by cutaneous tumours may enable them to escape host defence mechanisms and to invade surrounding tissue. Immunohistochemical studies in a wide range of epidermally derived tumours demonstrated expression by keratinocytes of the class II molecule HLA-DR in squamous cell carcinoma (SCC) (2 of 8 cases) and keratoacanthoma (KA) (2 of 7 cases). Additionally, HLA-DP and DQ were expressed by single cases of SCC and KA, although, unlike the widespread distribution of DR, DP and DQ, were only present on keratinocytes adjacent to the inflammatory infiltrate. Therefore, keratinocytes in cutaneous tumours, like carcinoma cells of the colon and breast, may express class II MHC antigens during tumour growth. Beta-2-microglobulin (B2M), an invariant MHC class I marker, was absent in all cases of basal cell carcinoma. Variable loss of B2M was observed in squamous cell carcinoma, Bowen's disease and actinic keratoses, suggesting reduced B2M expression by dysplastic cells. However, the variability in B2M staining both between and within diagnostic categories restricts it's immunodiagnostic usefulness.

Antigens, Neoplasm↗
PubMed1999

Biological effects of genes in the Grc and EC region of the rat major histocompatibility complex.

PROBLEM: To study the mechanism of action of major histocompatibility complex (MHC)-linked genes affecting reproduction, growth, and susceptibility to chemical carcinogens. METHOD OF STUDY: Tumors derived from rat embryonic fibroblasts were transfected with cosmids from the Grc and its linked regions, the unrelated A region, and a nonMHC region, or with genes from the Grc, Grc-linked, and nonMHC regions, to determine whether they could suppress tumor growth as determined by in vitro (soft agar) and in vivo assays. RESULTS: Tumor fibroblasts transfected with cosmids from the Grc or from the EC region decreased tumor growth in both the in vitro and in vivo assays. Transfection with individual genes from the Grc had no effect on tumor growth in either assay. CONCLUSIONS: The effects of the Grc on reproduction, growth, and tumorigenesis are mediated by extended genetic effects, i.e., by the conformation of the DNA in this region. Similar effects were seen following transfection with cosmids from the Grc-linked EC region, and this finding strengthens the hypothesis that the conformation of the DNA in this general region is critical for its function. A similar effect has been described for the locus control region (LCR) in the beta-globin gene family in the human.

Animals↗