Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene

Peijnenburg, Ad; Berg, R. Van den; Eggermond, M. J. C. A. Van; Sanal, Özden; Vossen, Jaak M.; Lennon, Ana Maria; Alcaïde‐Loridan, Catherine; Elsen, Peter J. van den

doi:10.1007/s002510050007

Cited by 24 publications

(17 citation statements)

References 30 publications

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“…The pGL3-control, containing an SV40 promoter upstream of the luciferase gene, and the promoterless pGL3-basic and pGL2-basic constructs were from Promega. The pGL3-DRA, pGL3-DQA, and pGL3-DPA plasmids contain 250-bp promoter fragments of the HLA-D genes, which include the conserved W, X1, X2, and Y boxes (41). The human CIITAp-D2 vector (42) containing the minimal promoter IV of CIITA cloned in the pGL2-basic vector was kindly provided by E. Benveniste (University of Alabama, Birmingham, AL).…”

Section: Cell Transfections Luciferase Constructs and Assaysmentioning

confidence: 99%

Constitutive Expression of MHC Class II Genes in Melanoma Cell Lines Results from the Transcription of Class II Transactivator Abnormally Initiated from Its B Cell-Specific Promoter

Deffrennes

Vedrenne

Stolzenberg

et al. 2001

The Journal of Immunology

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In melanoma cell lines, two different patterns of MHC class II expression have been described, either an IFN γ-inducible expression of HLA-DR and HLA-DP, with a faint or null expression of HLA-DQ, resembling that described for melanocytes, or a constitutive expression, i.e., IFN-γ independent, of all three HLA-D isotypes. As this latter phenotype has been associated with a more rapid progression of melanoma tumors, we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression. In agreement with the evidence of a coordinate transcription of the HLA-D genes in these cell lines, we have shown the constitutive expression of CIITA (class II transactivator) transcripts, CIITA being known as the master switch of MHC class II expression. Unexpectedly, these transcripts initiate from promoter III of the CIITA gene, a promoter that is mainly used constitutively in B lymphocytes. This expression was further shown to occur through factor(s) acting on the enhancer located upstream of CIITA promoter III, which was previously described in epithelioid cells as an IFN-γ-response sequence. The hypothesis of a general abnormality of the IFN-γ transduction pathway was dismissed. Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines, we propose the hypothesis that this phenomenon might not be a random event, but could be linked to the neoplasic state of the melanoma cells.

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Section: Cell Transfections Luciferase Constructs and Assaysmentioning

confidence: 99%

Constitutive Expression of MHC Class II Genes in Melanoma Cell Lines Results from the Transcription of Class II Transactivator Abnormally Initiated from Its B Cell-Specific Promoter

Deffrennes

Vedrenne

Stolzenberg

et al. 2001

The Journal of Immunology

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“…Lack of CIITA expression results in absence of MHC class II expression, whereas reduction in MHC class I expression can also be noted in some cell types. 7,27,28 Given the central role of CIITA in MHC-mediated antigen presentation, it may be hypothesized that inactivation of CIITA may be one of the mechanisms through which cells create an immune privilege and through which tumors may escape immunosurveillance. CIITA exerts its function in transactivation without binding directly to DNA of MHC class II and class I promoter regions but through protein-protein interactions with transcription factors bound directly to the MHC class II and class I promoters.…”

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confidence: 99%

Lack of ifn‐γ‐mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines

Stoep

Biesta

Quinten

et al. 2001

Intl Journal of Cancer

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The class II transactivator (CIITA) plays a pivotal role in the expression of major histocompatibility complex (MHC) class II and accessory genes (invariant chain [Ii] and HLA-DM), whereas it has an ancillary function in the expression of MHC class I and ␤ 2 -microglobulin (␤ 2 m) genes. 1-9 The MHC is a large multigene family that encodes cell surface glycoproteins involved in binding and presentation of antigenic peptides to T lymphocytes. The products of the ␤ 2 m, Ii and HLA-DM genes are also essential proteins in MHC class I-and class II-mediated antigen presentation function, respectively. For this reason CIITA-mediated MHC expression is central in the generation of an antigen-specific immune response by presenting antigenic peptides to the T-cell receptor (TCR) on T lymphocytes. 10,11 MHC class I molecules are expressed on almost all nucleated cells. In contrast, the constitutive expression of MHC class II molecules is restricted to specific immune cell types that include antigen-presenting cells such as dendritic cells, B lymphocytes, macrophages and thymic epithelial cells. Nonimmune cells lack constitutive expression of MHC class II; however, in most of these cells MHC class II expression can be induced by interferon-␥ (IFN-␥). 12,13 Notably, expression of MHC class I molecules can also be enhanced by IFN-␥. Together, the upregulated expression of MHC class I and class II molecules results in an increase in the immunogenic potential of cells. The importance of MHC expression by tumor cells in mounting an effective antitumor immune response has been shown in animal models for T-cell-mediated immunotherapy 14 -16 and is corroborated by the notion that tumors expressing high levels of both MHC class I and class II molecules display abundant lymphocytic infiltration. [17][18][19] Notably, patients with high tumorlytic lymphocyte infiltrates generally have a better prognosis. [17][18][19] Several tissues have been shown to exhibit a significantly reduced membrane expression of MHC class I molecules. In particular, certain reproductive and developmental tissues lack expression of MHC class I molecules, including sperm, 20 oocytes, 21 preimplantation embryos 22 and villous trophoblast cells. 23 The absence of MHC molecules from fetal and embryonic tissues creates an immune privilege for these cells during gestation and may be of functional significance during development. Also, several malignant cell types have been shown to lack the expression of MHC molecules. This reduced expression of MHC molecules will contribute to a decreased recognition by T cells, allowing an escape from immunosurveillance. 24 -26 Interestingly, most of the MHC-deficient tumor cells have originated from fetal or embryonic tissues. Downregulation of MHC gene expression in these embryonic or developmental tumors may therefore not result from the neoplastic transformation event but may instead reflect the characteristic silent state of MHC class I and class II genes during early development.To understand the mechanisms of downregulat...

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confidence: 99%

“…Patients lacking class II MHC have reduced numbers of CD4 ϩ Th cells and succumb to repeated bacterial, viral, and protozoal infections, generally dying in early childhood (39). Class II MHC has been implicated as a contributing factor for numerous diseases including diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis (7,39,49).The constitutive and inducible expression of nearly all class II MHC and related genes is regulated globally at the level of transcription by the class II transactivator (CIITA) (8,27,60). Transient transfection of CIITA into cells which are class II MHC deficient or have low-level expression of class II MHC is sufficient to drive class II MHC transcription and expression (12,46,48).…”

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confidence: 99%

Downregulation of CIITA Function by Protein Kinase A (PKA)-Mediated Phosphorylation: Mechanism of Prostaglandin E, Cyclic AMP, and PKA Inhibition of Class II Major Histocompatibility Complex Expression in Monocytic Lines

Harton

Zhu

et al. 2001

Molecular and Cellular Biology

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Prostaglandins, pleiotropic immune modulators that induce protein kinase A (PKA), inhibit gamma interferon induction of class II major histocompatibility complex (MHC) genes. We show that phosphorylation of CIITA by PKA accounts for this inhibition. Treatment with prostaglandin E or 8-bromo-cyclic AMP or transfection with PKA inhibits the activity of CIITA in both mouse and human monocytic cell lines. This inhibition is independent of other transcription factors for the class II MHC promoter. These same treatments also greatly reduced the induction of class II MHC mRNA by CIITA. PKA phosphorylation sites were identified using site-directed mutagenesis and phosphoamino acid analysis. Phosphorylation at CIITA serines 834 and 1050 accounts for the inhibitory effects of PKA on CIITA-driven class II MHC transcription. This is the first demonstration that the posttranslational modification of CIITA mediates inhibition of class II MHC transcription.Class II molecules of the major histocompatibility complex (MHC) play a critical role in T-cell-dependent immunity and the inflammatory response by presenting processed, exogenous antigens to T helper (Th) cells (reviewed in references 13, 42, and 50). These important molecules are commonly used as targets for immune therapies aimed at blocking graft rejection or promoting the recognition of cancer. Although expressed constitutively on "professional" antigen-presenting cells (monocytes/macrophages, B cells, and dendritic cells) class II MHC can be induced in most cell types and tissues in the presence of gamma interferon (IFN-␥) (1, 3, 9-11, 24, 28, 31, 38, 45, 57, 60, 62). Patients lacking class II MHC have reduced numbers of CD4 ϩ Th cells and succumb to repeated bacterial, viral, and protozoal infections, generally dying in early childhood (39). Class II MHC has been implicated as a contributing factor for numerous diseases including diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis (7,39,49).The constitutive and inducible expression of nearly all class II MHC and related genes is regulated globally at the level of transcription by the class II transactivator (CIITA) (8,27,60). Transient transfection of CIITA into cells which are class II MHC deficient or have low-level expression of class II MHC is sufficient to drive class II MHC transcription and expression (12,46,48). In normal tissues, CIITA expression patterns are controlled by as many as four promoters, which allow both constitutive and IFN-␥-inducible expression of CIITA (44, 52). Though not a DNA-binding protein, CIITA is required for the opening and subsequent activation of class II MHC promoters through interactions with the ubiquitously expressed transcription factors RFX and NF-Y, which recognize the X and Y DNA elements of class II and class I MHC promoters (41,54,64). CIITA contains an N-terminal acidic domain (residues 1 to 125) which can act as a transcription activation domain when fused to GAL4 DNA-binding sequences (34,54,63). A variety of proteins interact with the acidic do...

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Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene

Cited by 24 publications

References 30 publications

Constitutive Expression of MHC Class II Genes in Melanoma Cell Lines Results from the Transcription of Class II Transactivator Abnormally Initiated from Its B Cell-Specific Promoter

Constitutive Expression of MHC Class II Genes in Melanoma Cell Lines Results from the Transcription of Class II Transactivator Abnormally Initiated from Its B Cell-Specific Promoter

Lack of ifn‐γ‐mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines

Downregulation of CIITA Function by Protein Kinase A (PKA)-Mediated Phosphorylation: Mechanism of Prostaglandin E, Cyclic AMP, and PKA Inhibition of Class II Major Histocompatibility Complex Expression in Monocytic Lines

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