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PubMed1989

Transcriptional control of MHC class II gene expression during differentiation from B cells to plasma cells.

In this study we investigated the molecular mechanisms responsible for the extinction of the constitutive MHC class II gene expression of human B cells on somatic cell hybridization with murine plasmocytoma cells. We found that this event is due to trans-acting suppressor functions of mouse origin pre-existing in the plasmocytoma cells and acting at transcriptional level. Transcription of the entire family of human class II genes is suppressed, including genes as DO beta for which a distinct regulation of expression in B cells had been previously demonstrated. Suppression appears specific for class II genes because in the hybrids expression of MHC class I genes of mouse is unaffected and of human only partially reduced. Interestingly, also murine invariant chain gene is expressed in both parental plasmocytoma and hybrid cells although at reduced amounts as compared to a murine class II positive B cell line. The class II negative phenotype of hybrid cells and parental plasmocytoma cells is highly stable and unaffected by treatment with protein synthesis inhibitors, suggesting that the transcriptional suppressor function is not mediated by rapid, labile turning-over proteins. Possible mechanisms responsible for transcriptional regulation of MHC class II gene expression during terminal differentiation of B cells to plasma cells are discussed.

B-Lymphocytes↗
PubMed1995

Role of protein kinase C and tyrosine kinase activity in IFN-gamma-induced expression of the class II MHC gene.

Astrocytes are induced by interferon-gamma (IFN-gamma) to express class II major histocompatibility complex (MHC) antigens. Our previous studies demonstrated that IFN-gamma-initiated signaling events important for class II expression include activation of protein kinase C (PKC) and the Na+/H+ antiporter. We have extended these studies and found that protein tyrosine kinase (PTK) activity is also required for class II expression. Treatment of astrocytes with inhibitors specific for PKC and PTK blocked INF-gamma-induced class II gene transcription, mRNA expression, and protein expression. Immunoblotting and immunoprecipitation experiments demonstrated that IFN-gamma induced tyrosine phosphorylation of the p91 component of ISGF3, which is blocked by preincubation of cells with PTK inhibitors. Treatment of astrocytes with IFN-gamma and either PKC and PTK inhibitors changed the mobility and intensity of a nuclear factor, IFN-gamma-enhanced factor X, which binds to the X box of the class II MHC promoter. Taken together, these data provide evidence that activation of both PTK and PKC is required for IFN-gamma-induced expression of the class II gene.

Animals↗
PubMed1989

Transcriptional and post-transcriptional regulation of human MHC class II genes require the synthesis of short-lived proteins.

We have studied the stability of protein factors which control the intracellular levels of human MHC class II genes in B cells. We report that human MHC class II gene transcription and mRNA stability require the synthesis of short-lived proteins which undergo rapid intracellular turnover. We found, in fact, that the amount of MHC class II mRNA produced by human B lymphoma or B lymphoblastoid cell lines abruptly decreased upon cultivation of cells in the presence of cycloheximide, a potent inhibitor of protein synthesis. Measurements of the rate of mRNA transcription in nuclei isolated from treated cells indicated that a cycloheximide-sensitive activator protein is needed to allow MHC class II mRNA transcription initiation. Likewise, comparison of mRNA turnover rate in cells treated with actinomycin D, an inhibitor of RNA synthesis, and in cycloheximide-treated cells shows that a post-transcriptional factor is required to stabilized human MHC class II mRNA by a factor of 8- to 10-fold in B cells. These results indicate that, along with the trans- and cis-acting factors required for transcriptional control, a series of signals must exist in B cells which implement a post-transcriptional level of regulation of MHC class II gene expression in B cells.

Cell Line↗
PubMed1988

Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X.

The expression of MHC class II genes is tightly regulated. One form of congenital severe combined immunodeficiency (SCID) is characterized by a regulatory defect that precludes expression of HLA class II genes. B lymphocyte cell lines from such SCID patients provide a tool for identifying putative regulatory proteins that bind to class II gene promoters. We have identified three proteins binding to specific segments of the HLA-DRA promoter, two of which interact to form the predominant DNA-protein complex observed. One of these proteins, defined as an X box binding protein (RF-X), is specifically missing in cells from class II deficient SCID patients. We propose that the molecular defect in this congenital HLA class II regulatory deficiency is a lack of RF-X and that this factor plays an important role in the normal regulation of MHC class II gene expression.

B-Lymphocytes↗
PubMed2002

Locally derived cytokines and upregulation of MHC class II genes in allografts.

BACKGROUND: In vitro, various cytokines can modulate the level of expression of major histocompatibility complex (MHC) Class II antigens. Major histocompatibility complex Class II hyperexpression occurs in many immunologic disorders in vivo, but the cytokines that affect this are difficult to analyze because they are produced in small amounts, they act locally, and their mRNAs have short half-lives. METHODS: We studied the expression of cytokines known to up-regulate MHC Class II genes in heart allografts in mice from B10.BR donors to B10.D2 recipients by reverse transcription of mRNA and polymerase chain reaction amplification. The I-Abeta(k) gene expression was also studied in the same fully MHC incompatible strain combination. RESULTS: Messenger RNA for interferon (INF)-gamma, interleukin (IL)-4, and tumor necrosis factor (TNF)-alpha, known inducers of MHC Class II expression in vitro, could be detected in allografts either 24 hours before or simultaneously with massive induction of graft specific I-Abeta mRNA. Interleukin-6 mRNA could be detected as early as 1 day after grafting. CONCLUSION: These data suggest that known cytokine up-regulators of MHC Class II genes, i.e., IFN-gamma, IL-4, and TNF-alpha may contribute to the upregulation of graft-specific MHC Class II antigens during an allograft reaction. Also, IL-6 expression in allografts may result from the stress of the grafting procedure, as it is evident very early after grafting.

Animals↗
PubMedDate not supplied

Homing and immunogenicity of murine stromal cells transfected with xenogeneic MHC class II genes.

Syngeneic (murine) and xenogeneic (canine) marrow-derived stromal cells were injected intravenously into SCID and normal mice to examine the homing pattern and persistence of these cells in vivo. By in situ hybridization, these stromal cells were detectable in the bone marrow cavity and the spleen 21 days after injection. Xenogeneic cells did not persist in normal mice but persisted in SCID mice. Conditioning of the recipients with irradiation or 5-fluorouracil (5-FU) treatment did not alter these results. In addition, syngeneic murine stromal cells were transfected with the genes for canine MHC class II (DRA + DRB) and transplanted into murine recipients to investigate their homing pattern and immunogenicity. These transfected syngeneic stromal cells did also home to marrow and spleen even in normal recipients. However, these cells led to sensitization of the host towards canine antigens as shown by accelerated skin graft rejection and delayed type hypersensitivity (DTH). Thus, immunodeficient (SCID) mice allow for the homing of xenogeneic stromal cells to hemopoietic organs and for prolonged persistence. In immunocompetent (normal) mice, no xenogeneic stromal cells were identified in spleen and marrow, either because of their inability to home or more likely because of immunological rejection. In contrast, syngeneic stromal cells expressing xenogeneic MHC class II genes did home to spleen and marrow and persisted even though the recipient had become sensitized. Their survival may be due to a loss of expression of the transfected gene. Alternatively, the presentation of these xenogeneic gene products in the hemopoietic organs was such that a cytotoxic response was not induced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Regulation of class II MHC gene expression by macrophages from Bcgr and Bcgs mice.

The presence of class II mRNA was determined following stimulation of macrophages from Bcgr and Bcgs mice with rIFN-gamma. Despite the continuous expression of surface I-A glycoprotein by macrophages from Bcgr mice, class II mRNA was no longer present. The transient expression of I-A by macrophages from Bcgs mice, however, was accompanied by the disappearance of class II mRNA from the cells. Restimulation of macrophages from Bcgs mice, with rIFN-gamma resulted in the reappearance of class II mRNA and surface I-A expression. The reappearance of class II mRNA and the surface expression of I-A glycoprotein was inhibited by PGE2. These results indicate that differences in I-A expression by macrophages from Bcgr and Bcgs are not at the level of class II gene expression.

Animals↗
PubMed1986

Bone marrow-derived macrophage expression of endogenous and transfected class II MHC genes during differentiation in vitro.

C57BL/6 (H-2b) mice fail to express I-E molecules on the surface of their cells and thus are unable to respond to I-E-restricted antigens such as GL phi and cytochrome c. Previous experiments in our laboratory have involved developing a system for studying differentiation of bone marrow cells into mature macrophage to gain a better understanding of class II MHC gene expression and function. In this study, we have used this system to transfect the E alpha d gene (cosmid 17.2) into C57BL/6 bone marrow cells and subsequently observed I-E expression on bone marrow-derived macrophages (BMDM) after differentiation in vitro. By using a modified calcium phosphate protocol, we found that the optimal period for transfection of the bone marrow cells was after 2 days of culture in vitro. By using the anti-I-E monoclonal antibody (Ia.7) derived from hybridoma 14-4-4, we detected the I-E molecule on the surface of transfected macrophages by a radiobinding assay and immunoprecipitation. BMDM expressed the I-E product maximally at 5 days of differentiation, and expression then declined. Furthermore, we have found that the expression of the I-E molecule on transfected macrophage was dependent upon exposure to interferon-gamma. Expression of I-E molecules was also detected by the generation of an allogeneic response. Transfected BMDM were compared with (CB6)F1 BMDM for their ability to stimulate C57BL/6 T cells and they were found to be equally effective. By using these initial findings, we hope to further optimize the conditions for insertion and expression of class II MHC genes in bone marrow cells.

Animals↗
PubMed1999

Discoordinate expression of invariant chain and MHC class II genes in class II transactivator-transfected fibroblasts defective for RFX5.

MHC class II deficiency or bare lymphocyte syndrome is a severe combined immunodeficiency caused by defects in MHC-specific transcription factors. In the present study, we show that fibroblasts derived from a recently identified bare lymphocyte syndrome patient, SSI, were mutated for RFX5, one of the DNA-binding components of the RFX complex. Despite the lack of functional RFX5 and resulting MHC class II-deficient phenotype, transfection of exogenous class II transactivator (CIITA) in these fibroblasts can overcome this defect, resulting in the expression of HLA-DR, but not of DP, DQ, and invariant chain. The lack of invariant chain expression correlated with lack of CIITA-mediated transactivation of the invariant chain promoter in transient transfection assays in SSI fibroblast cells. Consequently, these CIITA transfectants lacked Ag-presenting functions.

Alleles↗
PubMed2000

Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection.

AIDS and the bare lymphocyte syndrome (BLS) are severe combined immunodeficiencies. BLS results from mutations in genes that regulate the expression of class II major histocompatibility (MHC II) determinants. One of these is the class II transactivator (CIITA). HIV and its transcriptional transactivator (Tat) also block the expression of MHC II genes. By binding to the same surface in the cyclin T1, which together with CDK9 forms the positive transcription elongation factor b (P-TEFb) complex, Tat inhibits CIITA. CIITA can also activate transcription when tethered artificially to RNA. Moreover, a dominant-negative CDK9 protein inhibits the activity of MHC II promoters. Thus, CIITA is a novel cellular coactivator that binds to P-TEFb for the expression of its target genes.

Animals↗
PubMed1995

Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency.

Type II major histocompatibility complex combined immune deficiency (type II MHC CID or bare lymphocyte syndrome) is a congenital immunodeficiency disease characterized by absent MHC class II expression. Four distinct complementation groups have been identified. Recently, the defective gene in group II type II MHC CID has been isolated and termed CIITA. Here, we demonstrate that CIITA is an MHC class II gene-specific transcription activator. The transcription activation function is provided by the N-terminal acidic domain (amino acids 26-137), which is experimentally exchangeable with a heterologous viral transcription-activating domain. The specificity of CIITA for three major MHC class II genes, DR, DQ and DP, is mediated by its remaining C-terminal residues (amino acids 317-1130). The transactivation of multiple cis elements, especially S and X2, of the DR alpha proximal promoter in group II CID cells is CIITA dependent. Since CIITA overexpression in normal cells did not increase class II expression, we propose that initiation of CIITA expression serves as the on-off switch, while availability of downstream interactor(s) limits transcription.

B-Lymphocytes↗
PubMed2004

Mini-review: Specificity and expression of CIITA, the master regulator of MHC class II genes.

The class II transactivator (CIITA) has been referred to as the "master control factor" for the expression of MHC class II (MHCII) genes. As our knowledge on the specificity and function of CIITA grows, it is becoming increasingly evident that this sobriquet is entirely justified. First, despite extensive investigations, the major target genes of CIITA remain those implicated in the presentation of antigenic peptides by MHCII molecules. Although other putative target genes have been reported, the contribution of CIITA to their expression remains indirect, controversial or comparatively minor relative to its decisive role as a regulator of MHCII and related genes. Second, the most important parameter dictating MHCII expression is by far the expression pattern of the gene encoding CIITA (MHC2TA). The vast majority of signals that activate or repress MHCII expression under physiological and pathological situations converge on one or more of the three alternative promoters that drive transcription of the MHC2TA gene. In short, with respect to its specificity and its exquisitely controlled pattern of expression, CIITA is by a long stretch the single most important transcription factor for the regulation of genes required for MHCII-restricted antigen-presentation.

Animals↗
PubMed1994

Physical mapping of the rat MHC class II genes shows a high level of interspecies conservation.

We report here a pulsed-field gel electrophoresis map of the rat major histocompatibility complex (MHC) class II region. Using probes for the recently discovered Tap-1 and Tap-2 genes and the different MHC class II genes, we found the gene order in the rat MHC (RT1) region to be RT1.H-Tap-1-Tap-2-Bb-Ba-Db-Da. Moreover, the distance between the Tap-1 and the RT1.Da genes is approximately 150 kb. This, together with recent mapping of the RT1 class II region, demonstrates an extensive colinearity in the MHC region of different species.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Differential expression of MHC class II genes in lung tumour cell lines.

Molecular characterization of HLA class II expression was investigated in five lung tumour cell lines at the protein and mRNA levels. The cell lines exhibited a differential expression of HLA-DR, HLA-DP and HLA-DQ products and also showed differences in the inducibility of HLA class II genes by gamma-IFN. Gamma-IFN stimulation induced only HLA-DR expression to varying degrees in three cell lines, while only one cell line showed stimulation for HLA-DP and none for HLA-DQ antigens. These results suggest locus-specific regulation for the three loci. The presence of DR protein on the cell-surface membrane was always positively correlated with the presence of HLA-DR mRNA in the cells. After treatment with 5-azacytidine in the A549 cell line, which expressed the lowest values, there was no effect on HLA class II levels. This suggested that methylation does not play an important role in the lack of MHC class II antigen expression. In addition to studying mRNA levels of HLA class II antigens, we analysed mRNA of the proto-oncogene c-myc and observed a positive correlation of two mRNA: the increments in HLA-DR expression were associated with increments in c-myc expression. This suggests a relationship between the regulatory and HLA-DR antigens control the expression of c-myc and HLA-DR antigens in lung tumour cell lines.

Actins↗
PubMed1995

How are class II MHC genes turned on and off?

Fragments of foreign antigen are detected by CD4+ helper T cells via the T cell receptor for antigen in the context of major histocompatibility complex (MHC) class II molecules. Very few cells normally express class II MHC molecules, and these cells play critical roles in antigen presentation and in the thymic selection of T lymphocytes before their exit into the periphery. Because of the central role the class II MHC molecules play in immune system function, it is not surprising that the lack of expression of these molecules results in a severe combined immunodeficiency disorder (called bare lymphocyte syndrome) and that the aberrant expression of the molecules is frequently observed in the target organs of various autoimmune disorders (e.g., multiple sclerosis and rheumatoid arthritis). Because both classes of disease could conceivably be treated by molecular approaches targeted at either restoring or inhibiting expression of class II MHC genes, there has been an intense effort during the past decade to elucidate the regulatory mechanisms of class II MHC genes. An analysis of recent advances in this effort is provided in this review article.

Animals↗