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At least 775 records · Page 43Linked to original sources
PubMed1990

Multiple nuclear factors interact with sequences within the J beta 2-C beta 2 intron of the murine T cell receptor beta-chain gene.

Identification of tissue-specific DNaseI hypersensitive sites in the TCR J beta 2-C beta 2 intron has suggested the presence of sequences involved in the regulation of gene expression. Therefore, we have searched for protein-DNA interactions within a 930-bp fragment derived from the J beta 2-C beta 2 intron by in vitro DNaseI protection experiments and electrophoretic mobility-shift assays. This analysis has revealed, in addition to a previously characterized NF-kappa B binding site, the presence of seven potential protein-DNA interaction sites within this fragment. Interestingly, they are clustered in the regions where in vivo T cell-specific nuclease hypersensitive sites have been previously identified. Binding sites for four potential transcription factors have been mapped precisely by methylation-interference experiments. Sequence comparisons show that one of them is homologous to the Y box present in the promoter regions of MHC class II genes. Identification of several protein-DNA interactions clustered within the J beta 2-C beta 2 intron and the presence of binding sites for two well-characterized transcription factors suggest a transcriptional regulatory function for this region.

Animals↗
PubMedDate not supplied

Allelic polymorphism in MHC class II B in four populations of Atlantic salmon (Salmo salar).

We sequenced exon 2 of the MHC class II B gene in Atlantic salmon from the Baltic Sea and identified 17 different exon 2 alleles among 22 different restriction fragment length polymorphism haplotypes. The sequences differed at between 1 and 34 bases. Two different tests were used to estimate the importance of recombination in the generation of new alleles. Recombination events appear to have occurred between three and nine times. Only two pairs of sequences differed by less than five nucleotides, minimizing the importance of point mutations for generating new alleles. Phylogenetic analysis showed that sequences did not cluster according to populations, and genetic distances between populations were small compared to those obtained by allele frequency data. These results, together with the similarity found between exon 2 sequences from Baltic salmon and Norwegian salmon, indicate that all of the identified alleles were present in the ancient salmon population colonizing the Baltic rivers after the last glaciation.

Alleles↗
PubMed1991

Identification of an immunodominant epitope within the phosphoprotein of rabies virus that is recognized by both class I- and class II-restricted T cells.

Immunization of H-2k mice with live rabies virus induces cytolytic T lymphocytes to the phosphoprotein of rabies virus. The antigenic determinant responsible for stimulating this class I-restricted cytolytic response was mapped to 50 amino acids (residues 180 to 229) of the phosphoprotein by using vaccinia virus recombinants expressing either the full-length phosphoprotein or C-terminal truncations of the phosphoprotein. The epitope was more finely mapped to residues 191 to 206 by using synthetic peptides. Several CD4+, class II-restricted T-cell lines were isolated from splenocytes of H-2k mice immunized with the vaccinia virus-rabies virus phosphoprotein recombinant virus. These lines were specifically stimulated by the phosphoprotein, and in addition, each line proliferated and released lymphokines in response to the same synthetic peptide shown to stimulate phosphoprotein-specific, class I-restricted cytolytic T cells.

Amino Acid Sequence↗
PubMed2002

Lack of IFN-gamma-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines.

Downregulation of major histocompatibility complex (MHC) molecules by tumor cells impairs cellular immune recognition and contributes to inefficient cell-mediated tumor eradication. Low or lack of expression of MHC molecules is frequently observed in early developmental or embryonically derived tumor cells. Considering the central role of the class II transactivator (CIITA) in MHC class II- and class I-mediated antigen presentation, we compared the induction of CIITA by interferon-gamma (IFN-gamma) in a diverse panel of developmental and more differentiated tumor cell lines. In contrast to the more differentiated tumor cell lines, none of the developmental tumor cell lines were capable of expressing CIITA after treatment with IFN-gamma. Remarkably, in transient transfection assays, CIITA promoter IV (CIITA-PIV) was found to be induced by IFN-gamma. Southern blot analysis of genomic DNA obtained from the developmental tumor cell lines indicated that the absence of endogenous CIITA induction was due to methylation of the CIITA-PIV region. Exposure to 5-azacytidine restored induction of CIITA and congruent HLA-DRA expression in these cells. The observation that only developmental tumor cell lines, originating from various tissues, employ methylation to silence CIITA expression may reflect the natural status of CIITA expression during early development rather than oncogenic transformation.

Azacitidine↗
PubMed1989

The octamer motif is a B-lymphocyte-specific regulatory element of the HLA-DR alpha gene promoter.

The human class II gene, HLA-DR alpha, contains an octanucleotide sequence ATTTGCAT located approximately 40 base pairs upstream of the transcription initiation site. We have investigated the transcriptional function of the DR alpha octamer in human B-lymphoblastoid cells and non-B cells. Deletion and substitution mutagenesis of the octamer sequence greatly reduced the activity of the DR alpha promoter in both in vivo and in vitro cell-free transcription systems of B-cell origin. Conversely, these mutations did not affect promoter activity in several non-B-cell lines that express the DR alpha gene. Removal of octamer-binding proteins by in vivo titration with an octamer-containing competitor plasmid reduced DR alpha promoter activity in B-lymphoblastoid cells. These results suggest that a protein-octamer interaction, most likely involving the B-cell-specific octamer binding protein (OTF-2), is required for DR alpha promoter function in B-lymphoblastoid cells but not in non-B cells.

B-Lymphocytes↗
PubMed1993

Mutant human cells defective in induction of major histocompatibility complex class II genes by interferon gamma.

Using immunoselection, we have isolated 11 independent mutant HT1080 fibrosarcoma cell lines defective in the induction by interferon gamma (IFN-gamma) of the expression of the human leukocyte antigen HLA-DRA. The mutations are recessive and fall into five complementation groups. All the mutants are affected mainly in the expression of major histocompatibility complex class II and invariant-chain genes. Type I mutants (three complementation groups) are completely defective in induction of the invariant-chain and class II HLA-DP, -DQ, -DR, and -DM genes, whereas type II mutants (two complementation groups) induce these genes weakly in response to IFN-gamma, in the order DPB > DRA > invariant chain. The induction by IFN-gamma of the mRNAs for class I, TAP1, LMP7, and 9-27 is partially defective and the induction of the proteins IRF-1 and ICAM-1 is normal in both types of mutants. All the mutants respond normally to IFN-alpha. The mutants are stable and thus can be used to clone the affected genes by reversion.

Antibodies, Monoclonal↗
PubMed1996

Use of flow cytometry and RT-PCR for detecting gene expression by single cells.

We have developed a method for reliably detecting gene expression by individual, phenotypically defined cells. Cells were sorted by flow cytometry into 96-well plates containing a Nonidet P-40 (NP40)-based bysis solution. Reverse transcription (RT) of cellular major histocompatibility complex class II DQB and either bovine leukemia virus (BLV) env or tax/rex mRNA was subsequently conducted using gene-specific oligonucleotide primers. Two sequential rounds of PCR were then performed to co-amplify DQB and either BLV env or tax/rex cDNA. The PCR products were electrophoresed in 6% polyacrylamide gels and visualized by ethidium bromide staining. The BLV-infected BL3 cell line was used to establish the sensitivity of the method; cellular and viral mRNA were reproducibly detected in wells into which single BL3 cells were sorted. Additionally, BLV env mRNA from single infected cells was consistently detected in reactions containing as many as 1000 uninfected cells. By using this method, 0.012% +/- 0.002% of B cells from a BLV-infected cow with persistent lymphocytosis were found to express BLV tax/rex mRNA, whereas < or = 0.001% expressed BLV env mRNA. The combination of single-cell sorting and RT-PCR provides a powerful new tool to study viral transcription, host responses associated with progression of retroviral infections or other problems requiring determination of the frequency of cells expressing a particular gene(s).

Animals↗
PubMed1997

Analysis of cytokine producing activity of intestinal intraepithelial T cells from TCR beta-chain and delta-chain mutant mice.

Intestinal intraepithelial T cells (IELs) expressing either gammadelta TCR or alphabeta TCR have been proposed to play an important role in the regulation of intestinal epithelia by producing cytokines that directly influence the adjoining intestinal epithelial cell (IEC) functions. To illuminate this issue, we utilized TCR mutant mice to obtain gammadelta IELs, alphabeta IELs and mixed gammadelta and alphabeta IELs from corresponding alphabeta T-cell-deficient (beta-/-), gammadelta T-cell-deficient (delta-/-) and wild-type (WT) littermate mice. The production of IFN-gamma by these IELs as well as the mRNA for IFN-gamma, TGF-alpha, TGF-beta1, TNF-alpha and TNF-beta in these IELs, in conjunction with the effect of produced cytokines on the expression of class II MHC molecules by the in vitro cell line IEC-6, were investigated. IFN-gamma and TNF-alpha [corrected] specific mRNA were detectable in all freshly isolated gammadelta, alphabeta and WT IELs. In addition to the IFN-gamma and TNF-alpha [corrected] mRNA, alphabeta and WT IELs that had been activated in culture plates coated with anti-CD3 mAb contained mRNA for TGF-beta1 and TNF-beta proteins. In the cultured gammadelta IELs, however, the signals for IFN-gamma and TNF-alpha [corrected] transcripts were weak, and mRNA for the latter two cytokines was almost undetectable. Supernatants from in vitro culturing of alphabeta and WT IELs but not gammadelta IELs induced class II MHC gene expression in IEC-6, whereas, in the presence of anti-IFN-gamma mAb, the same culture supernatants failed to do so. In fact, the concentration of IFN-gamma in supernatants from alphabeta and WT IEL cultures was ten- to twentyfold higher than that in the supernatant from the gammadelta IEL culture. Finally, TGF-alpha specific mRNA was not detectable in the gammadelta and alphabeta IELs even after in vitro activation. These results indicate that alphabeta IELs are superior to gammadelta IELs in the ability to produce IFN-gamma, TGF-beta1, TNF-alpha [corrected] and TNF-beta through TCR crosslinking primary in vitro stimulation.

Animals↗
PubMed1990

Differences in specificity of "DPw2-specific" cytotoxic T cell clones revealed with HLA-mutant lines: evidence that non-DP HLA genes influence recognition by some clones.

Seven allospecific cytotoxic T lymphocyte (CTL) clones derived from DPw2-specific bulk populations were characterized by three approaches to obtain a more detailed understanding of the T cell recognition of the HLA-DPw2 molecule. All seven of the clones were DPw2 specific and indistinguishable in specificity by three approaches: (a) patterns of lysis of panels of targets from normal donors; (b) inhibition of lysis by anti-class II monoclonal antibodies (mAb); (c) lysis of mutant lymphoblastoid B cell lines (LCL) with isolated loss of DP2 alpha or DP2 beta gene expression (as a result of selection for resistance to DPw2-specific CTL). However, only four of the seven CTL clones (which we designate "orthodox") lysed all mutant DPw2+ LCL tested; the other three ("heterodox") CTL clones showed reduced or no lysis of particular LCL which expressed DPw2 but had been mutagenized and selected for loss of DR expression. Cold target blocking experiments with the mutant LCL confirmed differences in: (a) specificity among CTL clones and (b) CTL-defined phenotype among serologically indistinguishable DR-DPw2+ mutant LCL. Differences were not explained by different levels of DP expression by the mutant LCL. Given the nature of the mutagens and mutations, it is highly improbable that point mutations in DP account for differences in recognition. These data suggest that non-DP HLA genes influence recognition by some DP-specific clones, potentially due to corecognition of HLA-DR alpha or another non-DP HLA product in the context of a DPw2 alpha/beta dimer.

Antibodies, Monoclonal↗
PubMed2003

Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice.

In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2(+) transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the alpha(1) and beta(1) domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-alpha and IFN-gamma) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients.

Amino Acid Sequence↗
PubMed1990

CD4+ CD45R- suppressor-inducer T-cell clones: requirements for cellular interaction, proliferation and lymphokines for the induction of suppression in peripheral blood mononuclear cells.

Regulation of the induction of suppressive activity in peripheral blood mononuclear cells (PBMC) by human major histocompatibility complex (MHC) class II+ CD4+ CD45R+ suppressor-inducer T-cell clones has been investigated. Previously, it was shown that in this system, cyclosporin A-sensitive precursors gave rise to allo-indifferent MHC-unrestricted CD4+ suppressive cells. Their induction could be blocked by monoclonal antibodies (mAb) to multilocus MHC class II gene products (TU 39) but not by mAb preferentially reacting with HLA-DR, -DQ or -DP molecules. This product, functionally defined, was termed 'DY'. It is shown here that induction of suppression by DY follows established activation pathways: (i) cell adhesion was required because CD11a (LFA-1) mAb blocked suppressor-induction; (ii) CD4 mAb also blocked, consistent with the involvement of class II products in suppressor-induction; (iii) cell proliferation was required because mAb to transferrin receptors, or irradiation, inhibited induction; and (iv) such proliferation appeared to be interleukin (IL)-2-dependent because it was blocked by mAb to IL-2 receptor, and enhanced by exogenous IL-2 but not IL-4. It was also enhanced by exogenous IL-1 and IL-6, but not by IL-3, tumour necrosis factor-alpha (TNF alpha) or interferon-gamma (IFN-gamma). It therefore seems that the requirements for activation of suppression by CD4+ DY+ T-cell clones in this in vitro model bear many similarities to those for CD4+ helper T cells, namely, mediation by MHC class II with CD4 involvement, dependency on LFA-1-influenced cell interactions, and reliance on clonal expansion caused by IL-2 and possibly amplified by IL-1 and/or IL-6.

CD4 Antigens↗
PubMed1985

Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen.

The 55 codons upstream of the gene sequence encoding the hepatitis B surface antigen (HBsAg) are called the pre-S(2) region. It has been proposed that polypeptides of high molecular weight that contain the pre-S(2) region should be included in future hepatitis B virus (HBV) vaccines. The pre-S(2) region and the S gene product [25 kilodalton (kD)] together compose a polypeptide of high molecular weight (33 kD). As an initial attempt to determine the relevance of the 33-kD polypeptide to development of an HBV vaccine, the murine immune response to pre-S(2)-encoded determinants as compared to S-encoded determinants on the same polypeptide was examined. The results indicate (i) the pre-S(2) region is significantly more immunogenic than the S region of HBsAg, (ii) the 26 amino acid residues at the NH2-terminus of the 33-kD polypeptide represent a dominant antibody binding site on the pre-S(2) region, (iii) the immune response to the pre-S(2) region is regulated by H-2-linked genes distinct from those that regulate the response to the S region, and (iv) immunization of an S region nonresponder strain with HBV envelope particles that contain both the pre-S(2) and S regions can circumvent nonresponsiveness to the S region.

Amino Acid Sequence↗
PubMed1996

Proteolytic processing activates a viral superantigen.

Mouse mammary tumor virus (MMTV) superantigens (vSAg) undergo proteolytic processing at residues that have been demonstrated in vitro to be recognition sites for the endoprotease furin. To examine the role of furin in the presentation of vSAg7 to T cells, the vSAg7 and class II MHC IEk genes were introduced into Chinese Hamster Ovary (CHO) cells (furin-positive) and into a furin-negative CHO variant (FD11). Both transfected cell lines efficiently presented peptide antigen and bacterial superantigens to T cell hybridomas. However, while the furin-positive cells presented vSAg7 well, the furin-negative cells presented poorly. Transient transfection of the furin-negative cells with an expression plasmid containing the furin gene restored the ability to present vSAg7 efficiently. The marginal presentation of vSAg7 observed using the furin-negative transfectants was eliminated after culture with the protease inhibitor leupeptin, suggesting that one or more endoproteases other than furin have a detectable but limited capacity to proteolytically activate vSAg7. Biochemical analyses revealed that vSAg7 was largely unprocessed in the absence of furin. Thus, viral superantigens, unlike bacterial superantigens, require proteolytic processing to activate T cells.

Animals↗
PubMed2002

Genetic susceptibility and gastric cancer risk.

The aim of the present paper is to review and evaluate, in a comprehensive manner, the most recent published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. We have identified all studies available in MEDLINE published up to October 2001. Only studies carried out in humans and comparing gastric cancer cases with at least 1 standard control group were included in the analysis. We were able to find 31 articles based on 25 case-control studies carried out in Caucasian, Asian and African populations. Most of the studies assess the effect of genes involved in detoxifying pathways (n = 12) and inflammatory responses (n = 7). The most widely studied is the GSTM1 null polymorphism. Only a very few studies have evaluated the risk of gastric cancer associated with genes acting on mucosa protection, oxidative damage and DNA repair. The most consistent results are the increased gastric cancer risk associated with IL1B and NAT1 variants, which may account for up to 48% of attributable risk of gastric cancer. Only polymorphisms at HLA-DQ, TNF and CYP2E genes may confer some protective effect against gastric cancer. The most important limitations that preclude definitive conclusions are (i) the lack of appropriate control of potential sources of bias (only 5 population-based studies have been published so far); (ii) the low number of cases analyzed (14 studies included fewer than 99 cases); and (iii) the low number of studies (n = 3) offering concomitant analysis of genetic susceptibility and exposure to relevant cofactors (Helicobacter pylori infection, diet and smoking). We conclude that the scientific data on the role of genetic factors in gastric cancer risk are promising. The lack of association reported so far should be considered with caution due to significant limitations in study design. Cohort studies taking into account simultaneously the different genetic and environmental factors potentially involved in gastric tumorigenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contribution of their putative interactions.

Carcinogens↗
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↗
PubMed2000

Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter.

Scaffold molecules interact with multiple effectors to elicit specific signal transduction pathways. CIITA, a non-DNA-binding regulator of class II major histocompatibility complex (MHC) gene transcription, may serve as a transcriptional scaffold. Regulation of the class II MHC promoter by CIITA requires strict spatial-helical arrangements of the X and Y promoter elements. The X element binds RFX (RFX5/RFXANK-RFXB/RFXAP) and CREB, while Y binds NF-Y/CBF (NF-YA, NF-YB, and NF-YC). CIITA interacts with all three. In vivo analysis using both N-terminal and C-terminal deletion constructs identified critical domains of CIITA that are required for interaction with NF-YB, NF-YC, RFX5, RFXANK/RFXB, and CREB. We propose that binding of NF-Y/CBF, RFX, and CREB by CIITA results in a macromolecular complex which allows transcription factors to interact with the class II MHC promoter in a spatially and helically constrained fashion.

Animals↗