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PubMed1998

A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation.

There are numerous observations reporting that phagocytes expressing major histocompatibility complex (MHC) Class II molecules are associated with the central nervous system (CNS) in normal and pathological conditions. Although MHC Class II expression is necessary for antigen presentation to CD4 + T-cells, it is not sufficient and co-stimulatory molecules are also required. We review here recent in vivo studies demonstrating that the microglia and perivascular macrophages are unable to initiate a primary immune response in the CNS microenvironment, but may support secondary immune responses. Although in vitro studies show that microglia do not support a primary immune response leading to T-cell proliferation, they do show that microglia may protect the CNS from the unwanted attentions of autoreactive T-cells by inducing their apoptosis. The lack of cells in the CNS parenchyma with the ability to initiate a primary immune response has a cost, namely that pathogens may persist in the CNS undetected by the immune system.

Animals↗
PubMed2004

Assembly of major histocompatibility complex (MHC) class II transcription factors: association and promoter recognition of RFX proteins.

Major histocompatibility complex (MHC) class II genes are regulated at the transcriptional level by coordinate action of a limited number of transcription factors that include regulatory factor X (RFX), class II transcriptional activator (CIITA), nuclear factor Y (NF-Y), and cyclic AMP-response element binding protein (CREB). Here, the MHC class-II-specific transcription factors and CREB were expressed in insect cells with recombinant baculoviruses, isolated, and characterized by biochemical and biophysical methods. Analytical ultracentrifugation (AUC) has demonstrated that RFX is a heterotrimer. A heterodimer of RFX5 and RFX-AP was also observed. A high-affinity interaction (K(d) = 25 nM) between RFX5 and RFX-AP was measured by isothermal titration calorimetry (ITC), while the interaction between RFX-AP and RFX-ANK is at least an order of magnitude weaker. The biophysical data show that the interaction between RFX-AP and RFX5 is a key event in the assembly of the heterotrimer. Fluorescence anisotropy was used to determine protein-nucleic acid binding affinities for the RFX subunits and complexes binding to duplex DNA. The RFX5 subunit was found to drive recognition of the promoter, while the auxiliary RFX-AP and RFX-ANK subunits were shown to contribute to the specificity of binding for the overall complex. AUC experiments demonstrate that in the absence of additional subunits, monomeric RFX5 binds to X-box DNA with a 1:1 stoichiometry. Interactions between CREB, CIITA, and RFX in the absence of DNA were demonstrated using bead-based immunoprecipitation assays, confirming that preassociation with DNA is not required for forming the macromolecular assemblies that drive MHC class II gene expression.

Animals↗
PubMed1996

Interferon-gamma differentially regulates antigen-processing functions in distinct endocytic compartments of macrophages with constitutive expression of class II major histocompatibility complex molecules.

RAW264.7 cells were transfected to express constitutively the murine class II major histocompatibility complex (MHC-II) molecule, I-Ak. The resulting RAW.Ak cells presented HEL(46-61) peptide to 3A9 T hybridoma cells, but they were unable to process and present HEL protein in their resting state. However, IFN-gamma stimulation induced the ability of RAW.Ak to process and present HEL protein, with little effect on their ability to present HEL(46-61) peptide. Antigen catabolism showed little change with IFN-gamma stimulation, suggesting that the production of peptides was not the regulated step in the processing pathway. Furthermore, HEL(46-61) peptide delivered directly into lysosomes by acid-resistant liposomes was also presented only upon IFN-gamma stimulation, while the presentation of peptides delivered into endosomes by acid-sensitive liposomes showed a lesser dependence on IFN-gamma stimulation. Thus, IFN-gamma regulated the ability of peptides delivered into certain lysosomal compartments to meet with MHC-II molecules and form peptide-MHC complexes, or to transport subsequently to the plasma membrane. Two other antigens, ribonuclease A and haemoglobin, were processed by RAW.Ak cells without IFN-gamma stimulation, suggesting that these antigens could be processed by different mechanisms, perhaps in earlier endocytic compartments. Thus, different antigens may be processed in distinct endocytic compartments, and an IFN-gamma-regulated mechanism controls the rescue of peptides from lysosomal compartments for presentation at the plasma membrane.

Animals↗
PubMed1995

The three-dimensional structure of a class I major histocompatibility complex molecule missing the alpha 3 domain of the heavy chain.

Class I major histocompatibility complex (MHC) molecules are ternary complexes of the soluble serum protein beta 2-microglobulin, MHC heavy chain, and bound peptide. The first two domains (alpha 1, alpha 2) of the heavy chain create the peptide binding cleft and the surface that contacts the T-cell receptor. The third domain (alpha 3) associates with the T-cell co-receptor, CD8, during T-cell recognition. Here we describe the x-ray crystal structure of a human class I MHC molecule, HLA-Aw68, from which the alpha 3 domain has been proteolytically removed. The resulting molecule shows no gross morphological changes compared to the intact protein. A decameric peptide complexed with the intact HLA-Aw68 is seen to bind to the proteolized molecule in the conventional manner, demonstrating that the alpha 3 domain is not required for the structural integrity of the molecule or for peptide binding.

Amino Acid Sequence↗
PubMed1996

Trimeric interactions of the invariant chain and its association with major histocompatibility complex class II alpha beta dimers.

The invariant chain (I chain) associates with major histocompatibility complex class II alphabeta heterodimers upon synthesis, preventing them from binding peptides and unfolded proteins in the endoplasmic reticulum and directing class II transport to post-Golgi endosomal compartments. To assess which regions of the I chain are involved in binding class II molecules, we have studied proteolytic fragments of the I chain generated both by natural proteolytic degradation of alphabeta dimer-invariant chain complexes (alphabeta.I) within human B cells and by in vitro digestion of purified alphabeta middle dotI complexes with proteinase K. The 18-kDa luminal I chain fragment generated by proteinase K, called K3, remains associated with alphabeta dimers and retains the complex (alphabeta.K3) in a high molecular mass nonameric configuration. The N terminus of the K3 fragment was identified as glycine 110. This indicates that the K3 fragment lies outside of the class II-associated invariant chain peptide region (amino acids 81-104) of the I chain, shown to be important for initial alphabeta.I assembly. An N-terminal 12-kDa I chain fragment called p12, generated intracellularly, was also analyzed and was found to remain associated with alphabeta dimers in a high molecular mass form analogous to the nonameric alphabeta.I complex. These results demonstrate that at least two class II contact points exist along the length of the I chain and that different regions of the I chain can stabilize the alphabeta.I nonamer. Additional evidence suggests that the O-linked glycan(s) characteristic of the I chain is added to the short C-terminal region absent from the K3 fragment.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2001

Hydrophobic ligand binding by Zn-alpha 2-glycoprotein, a soluble fat-depleting factor related to major histocompatibility complex proteins.

Zn-alpha(2)-glycoprotein (ZAG) is a member of the major histocompatibility complex (MHC) class I family of proteins and is identical in amino acid sequence to a tumor-derived lipid-mobilizing factor associated with cachexia in cancer patients. ZAG is present in plasma and other body fluids, and its natural function, like leptin's, probably lies in lipid store homeostasis. X-ray crystallography has revealed an open groove between the helices of ZAG's alpha(1) and alpha(2) domains, containing an unidentified small ligand in a position similar to that of peptides in MHC proteins (Sanchez, L. M., Chirino, A. J., and Bjorkman, P. J. (1999) Science 283, 1914-1919). Here we show, using serum-derived and bacterial recombinant protein, that ZAG binds the fluorophore-tagged fatty acid 11-(dansylamino)undecanoic acid (DAUDA) and, by competition, natural fatty acids such as arachidonic, linolenic, eicosapentaenoic, and docosahexaenoic acids. Other MHC class I-related proteins (FcRn, HFE, HLA-Cw*0702) showed no such evidence of binding. Fluorescence and isothermal calorimetry analysis showed that ZAG binds DAUDA with K(d) in the micromolar range, and differential scanning calorimetry showed that ligand binding increases the thermal stability of the protein. Addition of fatty acids to ZAG alters its intrinsic (tryptophan) fluorescence emission spectrum, providing a strong indication that ligand binds in the expected position close to a cluster of exposed tryptophan side chains in the groove. This study therefore shows that ZAG binds small hydrophobic ligands, that the natural ligand may be a polyunsaturated fatty acid, and provides a fluorescence-based method for investigating ZAG-ligand interactions.

Binding Sites↗
PubMed1994

Calnexin retains unassembled major histocompatibility complex class I free heavy chains in the endoplasmic reticulum.

The assembly of major histocompatibility complex (MHC) class I molecules involves the association of heavy (H) chain with beta 2-microglobulin (beta 2m) and peptide. Unassembled class I H chains do not exit the endoplasmic reticulum (ER) and this is exemplified by the beta 2m-deficient human melanoma FO-1 where free class I H chains are unable to complete assembly. In pulse chase experiments involving FO-1 cells, unassembled free class I H chains were shown to be stably associated with calnexin (IP90/p88), a 90-kD integral membrane molecular chaperone of the ER. To establish a role for calnexin in mediating this retention, we transfected FO-1 cells with a cytoplasmic tail deletion mutant of calnexin. Since the cytoplasmic tail contains the ER retention motif, these mutant calnexin molecules leave the ER and progress to the cell surface. In these stable transfectants of FO-1, free class I H chains also exited the ER and trafficked to the cell surface with calnexin, thus establishing a role for calnexin in the quality control of MHC class I assembly through mediating the ER retention of incompletely assembled class I H chains.

Calcium-Binding Proteins↗
PubMed2005

Rat cytomegalovirus induces a temporal downregulation of major histocompatibility complex class I cell surface expression.

Herpesviruses are known to influence expression of major histocompatibility complex (MHC) class I molecules on the surface of infected cells using a variety of mechanisms. Downregulation of MHC class I expression prohibits detection and elimination of infected cells by cytotoxic T lymphocytes. To investigate the effect of rat cytomegalovirus (RCMV) infection on MHC class I expression, we infected immortalized and primary rat fibroblasts with RCMV and monitored surface expression of MHC class I molecules at various time-points postinfection. These experiments revealed a downregulation of MHC class I surface expression by RCMV, a phenomenon that has also been reported for human and murine CMV. However, in contrast to the other cytomegaloviruses, RCMV causes only a temporal downregulation of MHC class I, with a maximal decrease at 12 h postinfection. Unlike murine and human CMV, RCMV does not induce proteolytic degradation of MHC class I molecules. In RCMV-infected cells, the MHC class I molecules are stable, but their exit from the ER is delayed.

Animals↗
PubMed2004

Presentation of donor major histocompatibility complex class II antigens by dna vaccination prolongs heart allograft survival.

BACKGROUND: Donor major histocompatibility complex (MHC) antigens play an important role in both allograft rejection and tolerance. With the use of several animal models, it has been shown that presentation of donor antigens before transplantation can lead to allograft tolerance. Vaccination of animals with a DNA plasmid encoding an antigen enables highly efficient expression of the protein in vivo. METHODS: In this study, we used DNA vaccination delivered through intramuscular, intraperitoneal, or intravenous routes to indirectly present donor antigens and to determine the effect in the modulation of the allograft response. LEW.1A recipients of a LEW.1W heart allograft were treated before grafting by vaccination with a plasmid encoding the donor RT1.D MHC class II or RT1.A class I molecules. RESULTS: Only anti-MHC II vaccination significantly prolonged allograft survival compared with untreated rats. We observed a significant prolongation of heart allograft survival with the intramuscular route of injection, but surprisingly we found the intravenous and intraperitoneal routes to be the best. CONCLUSION: After transplantation the anti-donor cellular response was significantly decreased in vaccinated rats. This was accompanied by a significant reduction in interferon-gamma mRNA expression in the grafted hearts and T helper 1-type alloantibody production, indicating that the vaccination modifies the alloresponse against the grafts.

Animals↗
PubMed2004

A temporal analysis shows major histocompatibility complex loci in the Scandinavian wolf population are consistent with neutral evolution.

The major histocompatibility complex (MHC) has an integral role in the immune system, and hence diversity at its genes may be of particular importance for the health of populations. In large populations, balancing selection maintains diversity in MHC genes, but theoretical expectations indicate that this form of selection is absent or inefficient in small populations. We examine the level of diversity at three MHC class II loci in the wolf population of Scandinavia, a population naturally recolonized with a genetic contribution from as few as three founders, and in four neighbouring wolf populations. In the Scandinavian wolf population, two alleles were found for each locus and the distribution of alleles is compatible with their linkage into two haplotypes. Changes in the level of heterozygosity over time since recolonization demonstrate the effects of the proposed arrival of an immigrant wolf. The maintenance of diversity is shown to be compatible with a neutral, random allocation of alleles, in conjunction with crossing between packs. A total of 15 DRB1, seven DQA and 10 DQB1 alleles are found in four neighbouring wolf populations, with substantial sharing across populations. Even in these larger populations, bottlenecks and fragmentation with consequent genetic drift are likely to have resulted in few indicators for balancing selection and significant differentiation of populations.

Animals↗
PubMed2005

Major histocompatibility complex locus DRA polymorphism in the endangered Sorraia horse and related breeds.

The major histocompatibility complex (MHC) genes play well-defined roles in eliciting immune responses and combating infectious diseases. This genetic system is among the most polymorphic. The extent of genetic variation within a population has been directly correlated with fitness for many traits. The MHC class II locus DRA polymorphism was analysed in the endangered Sorraia horse, two other Portuguese and four New World horse breeds considered to be historically close to the Sorraia. Comparison of the Sorraia with other breeds demonstrated less MHC variation among Sorraia horses. If DRA polymorphism provides greater disease resistance, selective breeding to increase MHC polymorphism may increase fitness of this population.

Animals↗
PubMed2006

Inhibition of heavy chain and beta2-microglobulin synthesis as a mechanism of major histocompatibility complex class I downregulation during Epstein-Barr virus replication.

The mechanisms of major histocompatibility complex (MHC) class I downregulation during Epstein-Barr virus (EBV) replication are not well characterized. Here we show that in several cell lines infected with a recombinant EBV strain encoding green fluorescent protein (GFP), the virus lytic cycle coincides with GFP expression, which thus can be used as a marker of virus replication. EBV replication resulted in downregulation of MHC class II and all classical MHC class I alleles independently of viral DNA synthesis or late gene expression. Although assembled MHC class I complexes, the total pool of heavy chains, and beta2-microglobulin (beta2m) were significantly downregulated, free class I heavy chains were stabilized at the surface of cells replicating EBV. Calnexin expression was increased in GFP+ cells, and calnexin and calreticulin accumulated at the cell surface that could contribute to the stabilization of class I heavy chains. Decreased expression levels of another chaperone, ERp57, and TAP2, a transporter associated with antigen processing and presentation, correlated with delayed kinetics of MHC class I maturation. Levels of both class I heavy chain and beta2m mRNA were reduced, and metabolic labeling experiments demonstrated a very low rate of class I heavy chain synthesis in lytically infected cells. MHC class I and MHC class II downregulation was mimicked by pharmacological inhibition of protein synthesis in latently infected cells. Our data suggest that although several mechanisms may contribute to MHC class I downregulation in the course of EBV replication, inhibition of MHC class I synthesis plays the primary role in the process.

Cell Line, Transformed↗
PubMed2003

Placental extravillous cytotrophoblasts persistently express class I major histocompatibility complex molecules after human cytomegalovirus infection.

Human cytomegalovirus (HCMV) downregulates the class I major histocompatibility complexes (MHCs), HLA-A and -B, in infected fibroblasts to escape from antigen-specific cytotoxic T lymphocytes. The HCMV genes responsible for the downregulation of MHCs are US2, US3, US6, and US11, which encode type I membrane proteins working at the endoplasmic reticulum (ER). However, it is largely unknown whether HCMV downregulates the class I MHC molecules in placental extravillous cytotrophoblasts (EVT), which express HLA-C, -E, and -G to protect a semiallogenic fetus from maternal natural killer (NK) cells at the fetomaternal interface. Here, we report that differentiated EVT prepared from human first-trimester chorionic villi persistently express class I MHC molecules upon HCMV infection. When these US proteins were expressed in uninfected EVT, they were localized at the ER in the entire cytoplasm. However, subsequent HCMV infection resulted in dissociation of these US proteins from the ER, which relocated toward the cell membrane. In fibroblasts, these US proteins were localized at the ER before and after HCMV infection. These results suggest that the US gene products are not integrated into ER of HCMV-infected EVT and fail to downregulate class I MHC molecules.

Cell Differentiation↗
PubMed1991

Stereospecific alignment of the X and Y elements is required for major histocompatibility complex class II DRA promoter function.

The regulatory mechanisms controlling expression of the major histocompatibility complex (MHC) class II genes involve several cis-acting DNA elements, including the X and Y boxes. These two elements are conserved within all murine and human class II genes and are required for accurate and efficient transcription from MHC class II promoters. Interestingly, the distance between the X and Y elements is also evolutionarily conserved at 18 to 20 bp. To investigate the function of the invariant spacing in the human MHC class II gene, HLA-DRA, we constructed a series of spacing mutants which alters the distance between the X and Y elements by integral and half-integral turns of the DNA helix. Transient transfection of the spacing constructs into Raji cells revealed that inserting integral turns of the DNA helix (+20 and +10 bp) did not reduce promoter activity, while inserting or deleting half-integral turns of the DNA helix (+15, +5, and -5 bp) drastically reduced promoter activity. The loss of promoter function in these half-integral turn constructs was due neither to the inability of the X and Y elements to bind proteins nor to improper binding of the X- and Y-box-binding proteins. These data indicate that the X and Y elements must be aligned on the same side of the DNA helix to ensure normal function. This requirement for stereospecific alignment strongly suggests that the X- and Y-box-binding proteins either interact directly or are components of a larger transcription complex which assembles on one face of the DNA double helix.

Animals↗
PubMed1996

Evidence for the involvement of a nuclear NF-kappa B inhibitor in global down-regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells.

Diminished expression of major histocompatibility complex class I antigens on the surface of adenovirus type 12 (Ad12)-transformed cells contributes to their high tumorigenic potential by enabling them to escape immune recognition by cytotoxic T lymphocytes. This low class I antigen expression is due to a block in class I transcription, which is mediated by Ad12 E1A. Genetic analysis has shown that the class I enhancer is the target for transcriptional down-regulation. In this study, we show that the ability of the R1 element of the class I enhancer to stimulate transcription is greatly reduced in Ad12-transformed cells. The loss of functional activity by the R1 element was attributed to loss of binding by the NF-kappa B p50-p65 heterodimer. NF-kappa B binding appears to be blocked within the nucleus rather than at the level of nuclear translocation. Significantly, NF-kappa B binding activity could be recovered from the nuclear extracts of Ad12-transformed cells following detergent treatment, suggesting that the block is mediated through a nuclear inhibitor present in the Ad12-transformed cells. These results, taken together with the fact that the R2 element of the class I enhancer exhibits strong binding to the transcriptional repressor COUP-TF, suggest that the class I enhancer is globally down-regulated in Ad12-transformed cells.

Adenoviruses, Human↗
PubMed1996

The major histocompatibility complex class II Ea promoter requires TFIID binding to an initiator sequence.

The major histocompatibility complex (MHC) class II Ea promoter is dependent on the presence of conserved upstream X and Y boxes and of initiator (Inr) sequences. In vitro transcription analysis of the Inr region with linker-scanning mutants pinpoints a functionally essential element that shows homology to the terminal deoxynucleotidyltransferase (TdT) Inr; contrary to the TdT Inr and other Inrs identified so far, the key sequence, between positions +5 and +12, is located within a transcribed area. Swapping the TdT sequence into the corresponding Ea position leads to a fivefold increase in transcription rate, without altering start site selection. Inr-binding proteins LBP-1/CP2 and TIP--a TdT Inr-binding protein unrelated to YY1--recognize the Ea Inr; they interact with overlapping yet distinct sequences around the Cap site, but their binding does not coincide with Ea Inr activity. A good correlation is, rather, found with binding of immunopurified holo-TFIID to this element. TFIID interacts both with Ea TATA-like and Inr sequences, but only the latter is functionally relevant. Unlike TBP, TFIID binds in the absence of TFIIA, indicating a stabilizing role for TBP-associated factors in Ea promoter recognition. Sequence comparison with other mouse and human MHC class II promoters suggests a common mechanism of start site(s) selection for the MHC class II gene family.

Animals↗
PubMed2001

Expression of the three human major histocompatibility complex class II isotypes exhibits a differential dependence on the transcription factor RFXAP.

Major histocompatibility complex class II (MHCII) molecules play a pivotal role in the immune system because they direct the development and activation of CD4(+) T cells. There are three human MHCII isotypes, HLA-DR, HLA-DQ, and HLA-DP. Key transcription factors controlling MHCII genes have been identified by virtue of the fact that they are mutated in a hereditary immunodeficiency resulting from a lack of MHCII expression. RFXAP-one of the factors affected in this disease-is a subunit of RFX, a DNA-binding complex that recognizes the X box present in all MHCII promoters. To facilitate identification of conserved regions in RFXAP, we isolated the mouse gene. We then delimited conserved domains required to restore endogenous MHCII expression in cell lines lacking a functional RFXAP gene. Surprisingly, we found that 80% of RFXAP is dispensable for the reactivation of DR expression. Only a short C-terminal segment of the protein is essential for this isotype. In contrast, optimal expression of DQ and DP requires a larger C-terminal segment. These results define an RFXAP domain with an MHCII isotype-specific function. Expression of the three MHCII isotypes exhibits a differential requirement for this domain. We show that this is due to a differential dependence on this domain for promoter occupation and recruitment of the coactivator CIITA in vivo.

Amino Acid Sequence↗
PubMed1989

NF-kappa B binds within a region required for B-cell-specific expression of major histocompatibility complex class II gene E alpha d.

A region upstream of the murine major histocompatibility complex gene, E alpha d, has been shown previously to be required for B-cell expression. Binding of the B-cell-specific factor, NF-kappa B, to a site within this region is indistinguishable from that observed with the kappa enhancer binding site. NF-kappa B may be responsible for E alpha d B-cell expression.

Animals↗