Expression of MHC II genes

Department of Medicine, Rosalind Russell Medical Research Center, University of California, San Francisco 94143, USA.
Current topics in microbiology and immunology (Impact Factor: 4.1). 02/2005; 290:147-70.
Source: PubMed


Innate and adaptive immunity are connected via antigen processing and presentation (APP), which results in the presentation of antigenic peptides to T cells in the complex with the major histocompatibility (MHC) determinants. MHC class II (MHC II) determinants present antigens to CD4+ T cells, which are the main regulators of the immune response. Their genes are transcribed from compact promoters that form first the MHC II enhanceosome, which contains DNA-bound activators and then the MHC II transcriptosome with the addition of the class II transactivator (CIITA). CIITA is the master regulator of MHC II transcription. It is expressed constitutively in dendritic cells (DC) and mature B cells and is inducible in most other cell types. Three isoforms of CIITA exist, depending on cell type and inducing signals. CIITA is regulated at the levels of transcription and post-translational modifications, which are still not very clear. Inappropriate immune responses are found in several diseases, including cancer and autoimmunity. Since CIITA regulates the expression of MHC II genes, it is involved directly in the regulation of the immune response. The knowledge of CIITA will facilitate the manipulation of the immune response and might contribute to the treatment of these diseases.

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    • "Finally, within the patterns of ageing effects in healthy gingival tissues , nuclear factors that have a role in both MHC-I and MHC-II functions were significantly increased. The CIITA (class II, major histocompatibility complex, transactivator ), which is up-regulated in ageing tissues, is a transcriptional co-activator that translocates to the nucleus and acts as an essential positive regulator of MHC-II gene transcription (Drozina et al. 2005). Mutations in this gene severely compromise the immune system and increase susceptibility to rheumatoid arthritis and multiple sclerosis (Friese et al. 2005). "
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    ABSTRACT: Gingival tissues of periodontitis lesions contribute to local elevations in mediators, including both specific T cell and antibody immune responses to oral bacterial antigens. Thus, antigen processing and presentation activities must exist in these tissues to link antigen-presenting cells with adaptive immunity. We hypothesized that alterations in the transcriptome of antigen processing and presentation genes occur in aging gingival tissues and that periodontitis enhances these differences reflecting tissues less capable of immune resistance to oral pathogens. Rhesus monkeys (n=34) from 3-23 years of age were examined. A buccal gingival sample from healthy or periodontitis sites were obtained, total RNA isolated, and microarray analysis was used to describe the transcriptome. The results demonstrated increased transcription of genes related to the MHC class II and negative regulation of NK cells with aging in healthy gingival tissues. In contrast, both adult and aging periodontitis tissues showed decreased transcription of genes for MHC class II antigens, coincident with up-regulation of MHC class I-associated genes. These transcriptional changes suggest a response of healthy aging tissues through the class II pathway (i.e., endocytosed antigens) and altered responses in periodontitis that could reflect host-associated self-antigens or targeting cytosolic intracellular microbial pathogens. This article is protected by copyright. All rights reserved.
    Journal Of Clinical Periodontology 12/2013; 41(4). DOI:10.1111/jcpe.12212 · 4.01 Impact Factor
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    • "While CIITA does not directly bind MHC II promoters, its association with the pre-assembled enhanceosome complex is required for MHC II expression and serves to coordinate steps leading to transcriptional initiation [12], [13]. CIITA recruits to MHC II promoters, including the HLA-DRA proximal promoter utilized in this study, components of the basal transcriptional machinery, histone acetyltransferases (HATs), histone deacetylases (HDACs), chromatin remodeling complexes, and kinases that phosphorylate RNA pol II [14], [15], [16], [17], [18], [19]. "
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    ABSTRACT: One mechanism frequently utilized by tumor cells to escape immune system recognition and elimination is suppression of cell surface expression of Major Histocompatibility Class II (MHC II) molecules. Expression of MHC II is regulated primarily at the level of transcription by the Class II Transactivator, CIITA, and decreased CIITA expression is observed in multiple tumor types. We investigate here contributions of epigenetic modifications to transcriptional silencing of CIITA in variants of the human breast cancer cell line MDA MB 435. Significant increases in histone H3 lysine 27 trimethylation upon IFN-γ stimulation correlate with reductions in transcription factor recruitment to the interferon-γ inducible CIITA promoter, CIITApIV, and with significantly increased CIITApIV occupancy by the histone methyltransferase enhancer of zeste homolog 2 (EZH2). Most compelling is evidence that decreased expression of EZH2 in MDA MB 435 variants results in significant increases in CIITA and HLA-DRA mRNA expression, even in the absence of interferon-γ stimulation, as well as increased cell surface expression of MHC II. Together, these data add mechanistic insight to prior observations of increased EZH2 expression and decreased CIITA expression in multiple tumor types.
    PLoS ONE 04/2012; 7(4):e36013. DOI:10.1371/journal.pone.0036013 · 3.23 Impact Factor
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    • "Regulatory factor X 2 (RFX2) is an example of a transcription factor (TF) that may be part of such an intrinsic program of spermatocyte differentiation. The RFX family consists of 5 related proteins (RFX1-5) [reviewed in [7-10]]. RFX1-4 have conserved DNA binding domains, recognize the same consensus binding site and can generally form homo and heterodimers with one another via conserved carboxyl-terminal dimerization domains. "
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    ABSTRACT: Mammalian spermatogenesis involves formation of haploid cells from the male germline and then a complex morphological transformation to generate motile sperm. Focusing on meiotic prophase, some tissue-specific transcription factors are known (A-MYB) or suspected (RFX2) to play important roles in modulating gene expression in pachytene spermatocytes. The current work was initiated to identify both downstream and upstream regulatory connections for Rfx2. Searches of pachytene up-regulated genes identified high affinity RFX binding sites (X boxes) in promoter regions of several new genes: Adam5, Pdcl2, and Spag6. We confirmed a strong promoter-region X-box for Alf, a germ cell-specific variant of general transcription factor TFIIA. Using Alf as an example of a target gene, we showed that its promoter is stimulated by RFX2 in transfected cells and used ChIP analysis to show that the promoter is occupied by RFX2 in vivo. Turning to upstream regulation of the Rfx2 promoter, we identified a cluster of three binding sites (MBS) for the MYB family of transcription factors. Because testis is one of the few sites of A-myb expression, and because spermatogenesis arrests in pachytene in A-myb knockout mice, the MBS cluster implicates Rfx2 as an A-myb target. Electrophoretic gel-shift, ChIP, and co-transfection assays all support a role for these MYB sites in Rfx2 expression. Further, Rfx2 expression was virtually eliminated in A-myb knockout testes. Immunohistology on testis sections showed that A-MYB expression is up-regulated only after pachytene spermatocytes have clearly moved away from the tubule wall, which correlates with onset of RFX2 expression, whereas B-MYB expression, by contrast, is prevalent only in earlier spermatocytes and spermatogonia. With an expanding list of likely target genes, RFX2 is potentially an important transcriptional regulator in pachytene spermatocytes. Rfx2 itself is a good candidate to be regulated by A-MYB, which is essential for meiotic progression. If Alf is a genuine RFX2 target, then A-myb, Rfx2, and Alf may form part of a transcriptional network that is vital for completion of meiosis and preparation for post-meiotic differentiation.
    BMC Developmental Biology 12/2009; 9(1):63. DOI:10.1186/1471-213X-9-63 · 2.67 Impact Factor
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