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PubMed2002

Major histocompatibility complex class II transcriptional platform: assembly of nuclear factor Y and regulatory factor X (RFX) on DNA requires RFX5 dimers.

Major histocompatibility complex class II (MHC-II) genes are regulated in a B-cell-specific and gamma interferon-inducible manner. Conserved upstream sequences (CUS) in their compact promoters bind nuclear factor Y (NFY) and regulatory factor X (RFX) complexes. These DNA-bound proteins form a platform that attracts the class II transactivator, which initiates and elongates MHC-II transcription. In this report, we analyzed the complex assembly of these DNA-bound proteins. First, we found that NFY can interact with RFX in cells. In particular, NFYA and NFYC bound RFXANK/B in vitro. Next, RFX5 formed dimers in vivo and in vitro. Within a leucine-rich stretch N-terminal to the DNA-binding domain in RFX5, the leucine at position 66 was found to be critical for this self-association. Mutant RFX5 proteins that could not form dimers also did not support the formation of higher-order DNA-protein complexes on CUS in vitro or MHC-II transcription in vivo. We conclude that the MHC-II transcriptional platform begins to assemble off CUS and then binds DNA via multiple, spatially constrained interactions. These findings offer one explanation of why in the Bare Lymphocyte Syndrome, which is a congenital severe combined immunodeficiency, MHC-II promoters are bare when any subunit of RFX is mutated or missing.

Amino Acid Motifs↗
PubMed1988

Multiple regulatory regions on the 5' side of the mouse E alpha gene.

The function of the 5'-flanking region of the mouse major histocompatibility complex gene Ed alpha has been studied by deletion analysis with the chloramphenicol acetyltransferase gene as a transient expression marker in various cell lines. This analysis reveals the presence of several control regions on the 5' side of the gene. Sequences between base pair (bp) -873 and bp -353 have a negative function in human and mouse fibroblasts but not in the mouse macrophage line WEHI-3. Additional positive and negative elements have been mapped between bp -353 and bp -38. A gamma-interferon response region has been also identified within that sequence. the 5' and 3' boundaries of the gamma-interferon response region have been located between bp -164 and bp -43. Inducible human cell lines showed the same gamma-interferon response region endpoints with the mouse cell line WEHI-3. A DNA fragment spanning the equivalent region of the mouse Ed beta gene confers gamma-interferon inducibility to the simian virus 40 and alpha-globin promoters in an orientation-independent manner. We further provide evidence that the conserved sequence motifs on the 5' side of all major histocompatibility complex class II genes are indispensable for gamma-interferon induction.

Animals↗
PubMed1997

Induction of MHC class I expression by the MHC class II transactivator CIITA.

Major histocompatibility complex (MHC) class I-deficient cell lines were used to demonstrate that the MHC class II transactivator (CIITA) can induce surface expression of MHC class I molecules. CIITA induces the promoter of MHC class I heavy chain genes. The site alpha DNA element is the target for CIITA-induced transactivation of class I. In addition, interferon-gamma (IFNgamma)-induced MHC class I expression also requires an intact site alpha. The G3A cell line, which is defective in CIITA induction, does not induce MHC class I antigen and promoter in response to IFNgamma. Trans-dominant-negative forms of CIITA reduce class I MHC promoter function and surface antigen expression. Collectively, these data argue that CIITA has a role in class I MHC gene induction.

Breast Neoplasms↗
PubMed1989

MHC antigen induction by interferon gamma on cultured mouse pancreatic beta cells and macrophages. Genetic analysis of strain differences and discovery of an "occult" class I-like antigen in NOD/Lt mice.

This study provides a basis for understanding the wide variations reported in the literature in IFN-gamma inducibility of class II MHC antigens on murine beta cells. Inducibility is not an intrinsic property of all mouse beta cells, but instead depends upon strain- (and tissue-) specific response modifying factors. This was demonstrated by comparison of constitutive and IFN-gamma-induced class I and class II MHC gene products on cultured islet cell monolayers. Islet cultures were established from autoimmune diabetes-prone NOD/Lt mice, diabetes-resistant NON/Lt and CBA/J mice, as well as F1 hybrids between these latter two strains and NOD/Lt. Cultures of peritoneal macrophages (M phi) from each strain were established as controls. After 3 wk of culture (with incubation in the presence or absence of IFN-gamma during the last 6 d), constitutive expression as well as IFN-gamma induction of class I MHC antigen expression was demonstrated on NOD/Lt and NON/Lt islet cells by antibody plus complement-mediated cytotoxicity. Although CBA/J islets and M phi did not maintain constitutive class I or class II antigen expression in culture in the absence of IFN-gamma, class I H-2Kk antigen was IFN-gamma inducible. Whereas IFN-gamma-induced class II I-Ak antigen on CBA/J M phi, it failed to induce this antigen on CBA/J islets. In contrast, I-A antigens were IFN-gamma inducible on NOD/Lt and NON/Lt islets and M phi. In (CBA x NOD)F1 hybrids, loss of IFN-gamma inducibility of the I-ANOD product established that suppression was mediated by a trans-acting factor from the CBA/J genome. In the course of these studies, IFN-gamma inducibility of a crossreactive occult class I-like antigen on both NOD/Lt islet cell and M phi cultures was unexpectedly detected when mAb 28-13-3 (public specificity 39, reactive with H-2Kb,f) was used as a negative control. Although not detectable by cytofluorographic analysis of freshly isolated NOD/Lt splenic leukocytes, occult antigen could be induced on NOD/Lt peritoneal macrophages (M phi) cultured for 3 d in IFN-gamma. Time course of induction showed the occult antigen to be distinct from NOD/Lt class I and II gene products. In both islet cell and M phi cultures established from (CBA x NOD)F1 hybrids, trans-suppressive factor(s) from the CBA/J genome not only suppressed IFN-gamma-induced expression of I-ANOD, but additionally suppressed occult antigen induction. Backcross of F1 to both parental strains indicated that the occult locus was on Chr 17, tightly linked to MHC.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Cloning of the MHC class II DRB cDNA from the brushtail possum (Trichosurus vulpecula).

The cell-surface glycoproteins encoded by the major histocompatibility complex (MHC) bind to processed foreign antigens and present them to T lymphocytes. Two classes of MHC molecules and their corresponding gene sequences have been extensively studied in eutherian mammals and birds, but data on the marsupial MHC are limited. Marsupials split from eutherian mammals about 125 million years ago and represent a distinct branch in mammalian evolution. Here the cDNA cloning of MHC class II genes of the brushtail possums (Trichosurus vulpecula) is reported. The sequences obtained were found to be relatively conserved when compared to the red-necked wallaby (Macropus rufogriseus) and an South American marsupial, Monodelphis domestica. The T. vulpecula sequence shared an average overall sequence identity of 75.4% at the deduced amino acid level with M. rufogriseus and M. domestica, respectively.

Amino Acid Sequence↗
PubMed2002

Complete cDNA coding sequence of the HLA-DRB1*1405 allele.

Cloning report of complete coding region of HLA-DRB1*1405 has never appeared in the literature. We have isolated and sequenced it from a B cell line with a DRB1*1405/1502 genotype. The sequence information of this gene and previously published DRB1 genes for the other DR serotypes facilitated us to find that the cytoplasmic domain sequences of DRB1 genes fall into three groups. It is known that antigen presenting cells are differentially activated when products of different MHC class II genes are triggered. Functional analyses would discern if these allelic differences in the cytoplasmic domain are of functional significance.

Amino Acid Sequence↗
PubMed1991

Common variable immunodeficiency is associated with polymorphic markers in the human major histocompatibility complex.

Common variable immunodeficiency (CVI) is a heterogeneous condition characterized by arrest in B cell differentiation. A high frequency of null alleles of the C4 gene has been reported in patients with this disorder. We investigated the restriction fragment length polymorphisms (RFLP) of the MHC class II genes HLA-DRB, DQA, and DQB, the class III gene C4 and the tumour necrosis factor-alpha) (TNF-alpha) gene in 40 Caucasian patients. The results showed an increase in HLA-DR3 in patients (40% vs 30.5%), but, more significantly, there was a striking increase in the number of CVI patients who carried a deletion of the C4A gene (46% vs 25%). In both patients and controls there was strong allelic association between HLA-DR3 and C4A deletion, and HLA-DR3 and TNF-alpha. Our results suggest that genes present on an extended haplotype containing these three polymorphisms contribute to genetic susceptibility to CVI.

Adolescent↗
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↗
PubMed1998

Suppression of human anti-porcine T-cell immune responses by major histocompatibility complex class II transactivator constructs lacking the amino terminal domain.

BACKGROUND: The class II transactivator (CIITA) is a bi- or multifunctional domain protein that acts as a transcriptional activator and plays a critical role in the expression of MHC class II genes. We have previously demonstrated that a mutated form of the human CIITA gene, coding for a protein lacking the amino terminal 151 amino acids, acts as a potent dominant-negative suppressor of HLA class II expression. Porcine MHC class II antigens are potent stimulators of direct T-cell recognition by human CD4+ T cells and are, therefore, likely to play an important role in the rejection responses to transgenic pig donors in clinical xenotransplantation. We were, therefore, interested in examining mutated CIITA constructs for their effect on porcine MHC class II expression. METHODS: Stable transfectants of the porcine vascular endothelial cell line PIEC with mutated CIITA constructs were tested for SLA-DR and SLA-DQ induction by recombinant porcine interferon-gamma. Transient transfectants of the porcine B-cell line L23 with the mutated CIITA constructs were tested for the suppression of constitutive SLA-DR and SLA-DQ expression. T-cell proliferation studies were performed using highly purified human CD4+ T cells. RESULTS: In preliminary studies, we demonstrated that transfection of the PIEC line with full-length human CIITA constructs resulted in strong expression of SLA-DR and SLA-DQ antigens, thus establishing the cross-species effectiveness of human CIITA in the pig. The mutated human CIITA constructs were, therefore, tested in the pig. PIEC clones stably transfected with one of these constructs showed up to 99% suppression of SLA-DR and SLA-DQ antigen induction and marked suppression of SLA-DRA mRNA induction. Moreover, transient transfection of the porcine B-cell line L23 showed up to 90% suppression of constitutive SLA-DR and SLA-DQ antigen expression in 5-8 days. In functional studies, interferon-gamma-stimulated PIEC clones transfected with this mutated CIITA construct failed to stimulate purified human CD4+ T lymphocytes. CONCLUSION: Mutated human CIITA constructs are potent suppressors of porcine MHC class II expression.

Amino Acid Sequence↗
PubMed2002

Molecular characterization of expressed DQA and DQB genes in the California sea lion ( Zalophus californianus).

To date, there are no published MHC sequences from the California sea lion (Zalophus californianus), a thriving species that, by feeding high on the marine food web, could be a sentinel for disturbances in marine and coastal ecosystems. In this study, degenerate primers and RACE technology were used to amplify near-full-length (MhcZaca- DQB) and full-length (MhcZaca- DQA) expressed class II MHC gene products from the peripheral blood mononuclear cells of two California sea lions in rehabilitation. Five unique Zaca- DQA sequences and eight unique Zaca- DQB sequences, all encoding functional proteins, were identified in the two animals, indicating the presence of multiple DQ- loci in this species. An additional three Zaca- DQB sequences containing features compatible with pseudogenes or null alleles were also identified. Despite the identification of multiple DQA and DQB sequences, the degree of heterogeneity between them was extremely low. To confirm the limited degree of Zaca-DQ nucleotide variation between individuals, we used denaturing gradient gel electrophoresis to examine putative peptide binding region sequences from the peripheral blood leukocyte-derived RNAs of 19 wild-caught California sea lions from physically distinct populations. The pattern of Zaca-DQ sequence migration was identical between individuals and independent of geographical region. This apparent Zaca-DQ sequence identity between sea lions was confirmed by direct sequencing of individual bands. In combination, these findings raise important questions regarding immunogenetic diversity within this thriving species, and should prompt further research into the existence of a highly polymorphic sea lion class II MHC molecule with sequence features that support traditional peptide binding functions.

Alleles↗
PubMed1994

Molecular analysis of the pathogenesis of autoimmune insulitis in NOD mice.

Among diabetes-susceptibility genes in NOD mice, only Idd-1 has been clearly assigned: Idd-1 could be a gene complex composed of class II major histocompatibility complex (MHC) genes, I-A beta and I-E. Employing restriction fragment length polymorphism (RFLP) analysis and nucleotide sequencing, we revealed that ILI and CTS mice, which are nondiabetic but are derived from the same Jcl-ICR mice as NOD mice, share the same class II MHC genes with NOD mice suggesting that both ILI and CTS mice also possess susceptible Idd-1 genotype. This was supported by a breeding study. To compare the usage of T cell receptor (TCR) V beta genes in NOD mice with that in ILI mice, we employed quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) which revealed that TCR V beta usages of these mice were indistinguishable. RT-PCR method also revealed that the V beta transcript of T cells infiltrating into pancreas of NOD mice was not restricted but was rather diverse. Since NOD and ILI mice share the same class I and II MHC antigens, we performed lymphocyte transfer experiments between these mice to examine the mechanism by which ILI mice do not develop insulitis. The results of reciprocal transfer of lymphocytes from NOD to ILI-nu/nu mice or from ILI to young NOD mice suggest that ILI mice exhibit autoantigens responsible for the development of insulitis but do not possess T cells reacting with islets. Of the diabetes-susceptibility genes, only in the case of Idd-1 is there any evidence for the identity of the gene products. ILI mice should provide more information on the products of the other diabetes-susceptibility genes of NOD mice.

Amino Acid Sequence↗
PubMed1995

Advances in HLA genetics.

The major histocompatibility complex (MHC) is a genetic system of over 70 known genes that occupies the midportion of the short arm of the sixth chromosome (C6p) and spans about 4 million base pairs of DNA. The high-resolution typing of class I and class II MHC genes and the identification of genes between and near them has increased the definition of the genetic basis of immune responses and diseases of unknown etiology such as autoimmune diseases in man. Although there are many more genetic systems that participate in the rejection of tissues and in the immune response, the MHC plays a central role in tissue compatibility and immune response against cancer and infectious diseases. In this paper, the authors review evidence about the role of HLA polymorphism in the pathogenesis and development of cancer, infectious diseases, autoimmune diseases and transplantation.

Animals↗
PubMed1986

In vitro allostimulation of peripheral blood mononuclear cells generates autologous reactive T lymphocytes: analysis at the clonal level.

Cells from two siblings within family PER with a maternal crossing-over were used as responder and stimulator cells; they differed in class II MHC gene products. The responder cells were cloned and studied for their specificity. All the clones were T4+, most of them, were allospecific cytotoxic T-cell clones, some were only proliferative. Among the 62 clones that have been screened for their phenotype and function, we could expand, in our cloning system, two autoreactive T-cell clones specific for the self-class II MHC products. The results indicated that this autoreactivity was also observed in serum-free medium, which excludes any serum components susceptible to alter the self-class II MHC products. For the autorecognition, the two clones used the T3-Ti complex, and only one of them, the T4 structure.

Antibodies, Monoclonal↗
PubMed1992

The antigen-processing mutant T2 suggests a role for MHC-linked genes in class II antigen presentation.

.174xCEM.T2 (T2) is a human cell hybrid that has a large homozygous deletion within the MHC, including all of the functional class II genes. We have generated stable HLA-DR3 and H-2 I-Ak transfectants of T2 that express parental levels of class II molecules at the cell surface. T2.Ak transfectants fail to stimulate a hen egg lysozyme (HEL)-specific, I-Ak-restricted T cell when incubated with intact HEL. However, stimulation occurs if the appropriate HEL peptide is provided. The T2 cell line therefore has a defect in class II-restricted Ag processing. Biosynthetic studies demonstrate that the kinetics of I-Ak transport in T2.Ak are similar to the parental rates of transport, although the percentage of I-Ak molecules transported appears somewhat lower. I-Ak glycoproteins in T2.Ak associate normally with the I-chain, which appears to be proteolytically cleaved after transport through the Golgi apparatus in a similar fashion to that in the parent cell line, .174xCEM.T1 (T1). The DR alpha beta heterodimers in T2 differ from the parental phenotype in two ways. First, HLA-DR3 expressed in T2 does not have the epitope recognized by the DR3-specific mAb 16.23, although DR3 expressed in the parent does have the epitope. Second, the alpha beta subunits in the parent remain associated when exposed to SDS at room temperature, although those in T2 dissociate.

Epitopes↗
PubMed2002

Differential splicing generates Tvl-1/RFXANK isoforms with different functions.

Earlier studies have shown that Tvl-1 gives rise to at least two differentially spliced mRNAs, one of which (Tvl-S) encodes a protein that lacks amino acids 91-112. DNA binding of RFX complexes assembled in the presence of Tvl-S is impaired. As a result, Tvl-S does not support the expression of Class II major histocompatibility complex (MHC) genes. Here, we show that the reason Tvl-S is inactive as a transcriptional regulator of Class II MHC genes is that the RFX complexes assembled in the presence of Tvl-S are unstable. Additionally, we show that interferon-gamma, which induces Class II MHC gene expression in 293 cells, promotes a shift in the splicing pattern of RFXANK/Tvl-1 toward the transcriptionally active Tvl-L isoform, suggesting that differential splicing of Tvl-1 is a signal-regulated process. Finally, we show that Tvl-1 regulates the expression of non-MHC genes. One such gene encodes the ephrin receptor EphA3. Since both Tvl-L and Tvl-S are identical in their ability to induce the expression of EphA3, we conclude that Tvl-1 regulates the expression of non-MHC genes by RFX-independent mechanisms.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Nucleotide sequence of the ring3 gene in the class II region of the mouse MHC and its abundant expression in testicular germ cells.

The RING3 (NAT) gene is the first and only locus with no obvious function associated with the immune system in the class II region of the human major histocompatibility complex. This gene is a homologue of the Drosophila homeotic gene female sterile homeotic (fsh) and encodes a nuclear serine-threonine kinase. To study more about the physiological function of the RING3 gene, we isolated a mouse homologue from a genomic library, determined its gene structure, and investigated its expression profile. The mouse Ring3 gene spans approximately 8 kb and consists of 12 exons encoding a 798-amino-acid protein, sharing as high as 96% amino acid identity with the human RING3 protein. Northern hybridization revealed that the Ring3 gene abundantly produced 3.8- and 3.0-kb transcripts in the testis but was weakly expressed with 4.6- and 3.8-kb transcripts in somatic tissues. It appears that testis-specific 3.0-kb transcript gives rise to a smaller size Ring3 protein resulting from the usage of the second ATG codon for translational initiation compared to the almost ubiquitous 4.6-kb transcript. In RNAs isolated from fractionated testicular germ cells, the two testicular mRNAs were detected exclusively in the fractions containing a large population of round spermatids and pachytene spermatocytes. Furthermore, in situ hybridization on cross sections of seminiferous tubules in the testis showed that the expression of the Ring3 gene was initiated at the pachytene spermatocyte stage during meiosis and persisted throughout the round spermatid stage during spermiogenesis. These results suggest that the Ring3 gene plays an important role in spermatogenesis.

Amino Acid Sequence↗
PubMed1992

A homologue of the Drosophila female sterile homeotic (fsh) gene in the class II region of the human MHC.

The RING3 gene maps in the class II region of the human major histocompatibility complex, at a CpG island distal of the HLA-DNA gene. RING3 cDNAs were obtained from a T cell cDNA library and the longest (4 kb) was sequenced. The sequence contained an open reading frame encoding a protein of 754 amino acids. A screen of protein databases revealed striking homology between the RING3 protein and the Drosophila female sterile homeotic gene (fsh) which is implicated in the establishment of segments in the early embryo. Partial sequence homology was also observed with some other proteins involved in cell cycle control (CCG1), cell division (ftsA) and regulation of cell growth (gamma interferons). This highly conserved gene may play an important role in human development. In addition, its location in the MHC class II region may be related to some HLA-associated diseases.

Amino Acid Sequence↗