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At least 523 records · Page 29Linked to original sources
PubMed1998

CIITA B-cell-specific promoter suppression in MHC class II-silenced cell hybrids.

In this study, various sets of somatic cell hybrids, generated by the fusion of epithelial cell lines with B-lymphoblastoid cell lines, were analyzed for the expression of major histocompatibility complex (MHC) class II antigens. We first demonstrate, in human and mouse intraspecies hybrids, the coordinate suppression of MHC class II, Ii (invariant chain) and HLA-DM gene transcription, and the release of the silencing by the addition of interferon gamma. Using interspecies hybrids, the segregation of human chromosomes allowed us to establish that MHC class II extinction is linked to the presence in the hybrids of the chromosomes from the epithelial fusion partner. Moreover, our data provide evidence that the expression pattern of MHC class II mRNA is correlated with that of the class II transactivator (CIITA), suggesting that CIITA is the actual target of the silencing. To gain further insight into the suppression phenomenon we performed luciferase assays which show that silencing affects the activity of the B-cell-specific promoter of CIITA. These results therefore demonstrate that the MHC class II gene silencing in somatic cell hybrids is due to an active suppression of one of the promoters of the CIITA gene, mediated by the epithelial cell fusion partner.

Animals↗
PubMed1997

The importance of the back-signal from T cells into antigen-presenting cells in determining susceptibility to parasites.

It has long been known that certain MHC class II genes can dominantly suppress immune responses and so increase susceptibility to parasite infections, but the mechanism has been unclear. Recent work has revealed one way in which this form of suppression may operate, through gating by MHC class II molecules of the back-signal from activated T cells into macrophages. The two known suppressive genes of the mouse are expressed in macrophages more extensively than are other class II genes. This is associated with suppression of IL-4 production resulting, we infer, from overproduction in the macrophages of IL-12, the counter-cytokine to IL-4. The lack of IL-4 may itself be immunosuppressive, even for Th2 responses, and excess IL-12 can overinduce the antiproliferative cytokine IFN-gamma. Although this mechanism requires further substantiation, we believe that it offers a reasonable answer to an old conundrum.

Animals↗
PubMed1994

The origin of the primate Mhc-DRB genes and allelic lineages as deduced from the study of prosimians.

MHC class II genes of the DRB family were partially sequenced from 10 individuals representing six species of prosimians: Galago senegalensis, G. moholi, Otolemur garnetti, Loris tardigradus, Petterus (Lemur) fulvus, and Lemur catta. Altogether, 41 different genes were discerned, all distinct from genes identified previously. Comparative analysis of the sequences has led to the following conclusions. First, the DRB loci present in human populations diverged from one another before the divergence of prosimian and anthropoid primates. Second, major allelic lineages of the DRB1 locus, such as DRB1*03 (DRB1*13) and DRB1*04, were established more than 85 million years ago. Third, the DRB6 gene was inactivated before the separation of prosimians and anthropoids, and has remained a pseudogene for more than 85 million years. Fourth, the primate DRB region is structurally and functionally unstable. In Lemur catta, for example, all DRB genes have apparently been lost and their function taken over by DOB and/or DPB genes. DRB genes are, however, present in a related species, Petterus (Lemur) fulvus. Fifth, the prosimian DRB3 genes are all inactive; their function seems to have been taken over by new genes. Sixth, several of the prosimian DRB genes and pseudogenes have recently been duplicated. In Otolemur garnetti, for example, one chromosome carries at least three copies of the DRB3 pseudogene.

Alleles↗
PubMed2004

MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells.

Major histocompatibility complex (MHC) class II-restricted antigen presentation is essential for the function of dendritic cells (DCs). We show here that plasmacytoid DCs (pDCs) differ from all other DC subsets with respect to expression of CIITA, the 'master regulator' of MHC class II genes. The gene encoding CIITA is controlled by three cell type-specific promoters: pI, pIII and pIV. With gene targeting in mice, we demonstrate that pDCs rely strictly on the B cell promoter pIII, whereas macrophages and all other DCs depend on pI. The molecular mechanisms driving MHC class II expression in pDCs are thus akin to those operating in lymphoid rather than myeloid cells.

Animals↗
PubMed2001

Analysis of the sequence polymorphism within class II transactivator gene promoters.

The class II transactivator is a major transcriptional factor acting on the promoters of MHC class II genes. Transcription of the CIITA gene is driven by four alternative promoters, which exhibit cell-type-specific activity. The CIITA promoter III (PIII) is constitutively active in B cells, whereas promoter IV (PIV) becomes activated upon interferon-gamma activation. The aim of this study was to investigate whether these two promoters exhibit a sequence variability like the MHC class II promoters do. We isolated PIII and PIV fragments from healthy individuals and rheumatoid arthritis patients and screened them for sequence polymorphisms. Single base pair substitutions within the CIITA PIV were found in 9% of the individuals analyzed. The majority of the substitutions were located upstream of the known cis-acting elements of the promoter. PIII was non-polymorphic. To evaluate the functional relevance of the detected polymorphism we cloned variable PIV upstream of the luciferase reporter gene. Such prepared constructs were transfected into monocytes, melanoma and HeLa cells, which were subsequently stimulated with interferon-gamma. The analysis of promoter activities did not reveal significant differences in all three cell types. We conclude that the level of CIITA expression does not vary within the population. Thus the differences in the level of MHC class II expression, which are observed between individuals, stem for the polymorphisms of the MHC class II promoters themselves.

Animals↗
PubMed2001

Mammalian expression cloning of two human trophoblast suppressors of major histocompatibility complex genes.

PROBLEM: Human trophoblasts suppress interferon-gamma (IFN-gamma)-simulated expression of major histocompatibility complex (MHC) class II genes and thereby protect the conceptus from maternal immune attack. The mechanism of this suppression is poorly understood. METHOD OF STUDY: IFN-gamma-responsive HeLa cells were stably transfected with trophoblast cDNA expression libraries and screened by negative immunoselection with an antibody to HLA-DR. RESULTS: Two suppressor cDNAs were isolated. One encoded the untranslated RNA trophoblast STAT utron (TSU), which blocked STAT1 nuclear translocation and can theoretically form triplex RNA-DNA at the class II transactivator gene promoters. The other encoded the N-terminal 28 residues of chorionic somatomammotropin (hCS). TSU-related genes were detected in human and macaque but not in mouse, genomic DNA. CONCLUSIONS: The genetics of two human trophoblast MHC suppressors suggest that these functions have been gained in human placenta in recent evolutionary history. TSU and hCS play critical roles in suppression of MHC genes, which may lead to silencing by DNA methylation.

Amino Acid Sequence↗
PubMed2002

Aberrant expression of Fas ligand in mice deficient for the MHC class II transactivator.

The MHC class II transactivator (CIITA) is a critical regulator of MHC class II genes and other genes involved in the Ag presentation pathway. CIITA-deficient mice lack MHC class II expression on almost all APCs. In this study, we show that these mice also have aberrant Fas ligand expression on both CD4 T cells and B cells. We found that Fas ligand expression was greatly increased on CIITA-deficient CD4 T cells during the Th1 differentiation process. However, both CIITA-deficient and control Th1 effector cells up-regulated Fas ligand to similar levels if cells were reactivated. The introduction of CIITA into primary CD4 T cells via retroviral infection resulted in a reduction in the level of Fas ligand and delay in apoptosis after activation. Interestingly, activated B cells from the CIITA-deficient mice also showed increased levels of Fas ligand that could be to some degree inhibited by the introduction of IL-4.

Animals↗
PubMed1999

Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette-Guérin involves class II transactivator and depends on the Nramp1 gene.

The natural resistance associated macrophage protein 1 (Nramp1) gene determines the ability of murine macrophages to control infection with a group of intracellular pathogens, including Salmonella typhimurium, Leishmania donovani, and Mycobacterium bovis bacillus Calmette-Guérin (BCG). The expression of the resistant allele of the Nramp1 gene in murine macrophages is associated with a more efficient expression of several macrophage activation-associated genes, including class II MHC loci. In this study, we investigated the molecular mechanisms involved in IFN-gamma-induced MHC class II expression in three types of macrophages: those expressing a wild-type allele of the Nramp1 gene (B10R and 129/Mphi), those carrying a susceptible form of the Nramp1 gene (B10S), and those derived from 129-Nramp1-knockout mice (129/Nramp1-KO). Previously, we published results showing that Ia protein expression is significantly higher in the IFN-gamma-induced B10R macrophages, compared with its susceptible counterpart. In this paper, we also show that the higher expression of Ia protein in B10R cells is associated with higher I-Abeta mRNA expression, which correlates with a higher level of IFN-gamma-induced phosphorylation of the STAT1-alpha protein and subsequently with elevated expression of class II transactivator (CIITA) mRNA, compared with B10S. Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, consequently, in the inhibition of Ia induction. Therefore, our data explain, at least in part, the molecular mechanism involved in the inhibition of I-Abeta gene expression in M. bovis BCG-infected macrophages activated with IFN-gamma.

Animals↗
PubMed1995

Sequencing of an upstream region of the human HLA-DRA gene containing X' and Y' boxes.

In this paper we report the characterization of a newly sequenced 5' upstream region of the human HLA-DRA gene. We performed (i) search for transcription factor motifs, (ii) analysis of CpG display and observed/expected frequency ratios, (iii) search for regions homologous to the 5' upstream sequences of the murine EA gene, (iv) DNase I footprinting experiments and (v) electrophoretic mobility shift assays. Our results demonstrate the existence, in the HLA-DRA gene, of Y' and X' boxes highly homologous to the Y and X boxes present in MHC class II genes, but oriented in the opposite direction. These Y' and X' boxes have been conserved during the molecular evolution of both human HLA-DRA and murine EA genes. DNase I footprinting and gel retardation experiments suggest that the X' and Y' boxes of the HLA-DRA upstream gene region are specifically recognized by nuclear proteins that also bind to the X and Y boxes of the HLA-DRA proximal promoter, respectively.

Animals↗
PubMed1989

Molecular characterization of MHC class II antigens (beta 1 domain) in the BB diabetes-prone and -resistant rat.

The BB or BB/Worcester (BB/W) rat is widely recognized as a model for human insulin-dependent diabetes mellitus (IDDM). Of at least three genes implicated in genetic susceptibility to IDDM in this strain, one is clearly linked to the major histocompatibility complex (MHC). In an attempt to define the diabetogenic gene(s) linked to the MHC of the BB rat, cDNA clones encoding the class II MHC gene products of the BB diabetes-prone and diabetes-resistant sublines have been isolated and sequenced. For comparison, the beta 1 domain of class II genes of the Lewis rat (RT1L) were sequenced. Analysis of the sequence data reveals that the first domain of RT1.D beta and RT1.B beta chain of the BB rat are different from other rat or mouse class II sequences. However, these sequences were identical in both the BB diabetes-prone and BB diabetes-resistant sublines. The significance of these findings is discussed in relation to MHC class II sequence data in IDDM patients and in the nonobese diabetic (NOD) mouse strain.

Amino Acid Sequence↗
PubMed1985

Multiple class I and class II major histocompatibility complex allospecificities are generated with T cell receptor variable (V) domains created by a single Ti beta V gene family.

10 alloreactive cytotoxic T lymphocytes using REX Ti beta variable region (V) gene segments in formation of their antigen/major histocompatibility complex (MHC) T3-Ti receptor were selected, cloned, and characterized in an effort to examine the extent of receptor diversity created by this one V gene family. Multiple and distinct class II as well as class I allospecificities were generated from the formation of different Ti beta V domains. Five allospecificities were directed at various class I epitopes whereas the other five were directed at class II MHC gene products. The following conclusions were drawn: (a) Ti beta V genes do not segregate into those that encode class I and those that encode class II allospecificities; and (b) there is no restriction on the Ti beta V gene pool available to T4+ vs. T8+ T lymphocytes.

Animals↗
PubMed1988

Antiviral immunity induced by recombinant nucleoprotein of influenza A virus. I. Characteristics and cross-reactivity of T cell responses.

The gene for the nucleoprotein of the A/NT/60/68 influenza virus was expressed in bacteria and the recombinant protein purified. Lymph node cells from mice immunized with recombinant nucleoprotein proliferated in response to in vitro stimulation with a range of type A influenza viruses. Proliferation was inhibited by mAb to CD4 and class II MHC gene products. IFN-gamma was produced and type-specific CTL were generated in stimulated cultures of immune lymph node cells. These CTL were CD4+ and restricted to class II MHC gene products. Immunization with recombinant nucleoprotein generated Th cells in vivo as measured by the ability to generate an accelerated response to hemagglutinin after challenge with inactivated virus. The results are discussed with reference to a cross-reactive vaccine against influenza.

Animals↗
PubMed1988

Characterization of cells comprising murine thymocyte multicellular complexes.

Characterization of complexes between thymocytes and thymic stromal cells was facilitated in the present study by demonstrating that complexes would reform if cells were incubated for 1.5 to 2 h in vitro at ambient temperature. Several immunologic approaches were used to determine the phenotype of complexed cells. Bound T cells were 97% double-positive (CD4 and CD8), 3% double-negative and greater than 99% CD3 positive by using immunoperoxidase immunohistology on cytospins. Five percent expressed the TCR beta-chain and 1 to 2% were IL-2R positive. The percentages were the same whether complexes were preformed in vivo or formed in vitro. Despite the apparent absence of single positive cells in complexes, when isolated CD4 or CD8 positive cells were tested for their ability to bind to adherent thymic macrophages, each subpopulation contained some cells which were capable of complex formation. When thymocytes were fractionated by density, steroid sensitivity or peanut agglutinin positivity then allowed to form complexes, cells with an immature phenotype had a greater propensity for complex formation. Central stromal cells all were class II MHC gene product (I-A and I-E) positive, expressed macrophage-associated Ag (B23.1 and MAC-1), were negative for cytokeratin but positive for vimentin, were reactive with a polyclonal antimacrophage serum, but did not express dendritic cell Ag (33D1). The data demonstrate that immature thymocytes bind exclusively to class II MHC gene product positive thymic macrophages. This binding step may play a role in the acquisition of T cell function in the thymus.

Animals↗
PubMed2003

DEK binding to class II MHC Y-box sequences is gene- and allele-specific.

Using electrophoretic mobility shift assays, we examined sequence-specific binding of DEK, a potential autoantigen in juvenile rheumatoid arthritis, to conserved Y-box regulatory sequences in class II MHC gene promoters. Nuclear extracts from several cell lines of different phenotypes contained sequence-specific binding activity recognizing DRA, DQA1*0101, and DQA1*0501 Y-box sequences. Participation of both DEK and NF-Y in the DQA1 Y-box binding complex was confirmed by 'supershifting' with anti-DEK and anti-NF-Y antibodies. Recombinant DEK also bound specifically to the DQA1*0101 Y box and to the polymorphic DQA1*0501 Y box, but not to the consensus DRA Y box. Measurement of the apparent dissociation constants demonstrated a two- to fivefold difference in DEK binding to the DQA1 Y-box sequence in comparison with other class II MHC Y-box sequences. Residues that are crucial for DEK binding to the DQA1*0101 Y box were identified by DNase I footprinting. The specific characteristics of DEK binding to these related sequences suggests a potential role for DEK in differential regulation of class II MHC expression, and thus in the pathogenesis of juvenile rheumatoid arthritis and other autoimmune diseases.

Alleles↗
PubMed1984

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12 neonatal females. Results of double thymus (B6 and bm12) engraftment excluded the possibility that this latter effect was caused by suppression. In addition, athymic bm1 mice were engrafted with thymuses from either B6 (Sendai CTL responder type) or syngeneic bm1 neonates (Sendai CTL nonresponder type). Again, both types of neonate thymuses restored T cell competence as measured by MHC/CTL responses to allogeneic cells. However, neither responder B6 nor nonresponder bm1 neonate thymus grafts allowed maturation of Sendai-specific CTL. In conclusion, the thymus dictates MHC specificity and immune response gene phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.

Animals↗
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↗
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↗