Revisiting the specificity of the MHC class II transactivator CIITA <i>in vivo</i>

Otten, L.; LeibundGut‐Landmann, Salomé; Huarte, Joachim; Kos-Braun, Isabelle C; Lavanchy, Christine; Barras, Emmanuèle; Borisch, Bettina; Steimle, Viktor; Acha‐Orbea, Hans; Reith, Walter

doi:10.1002/eji.200535687

Cited by 18 publications

(18 citation statements)

References 30 publications

(125 reference statements)

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“…3b). Consistent with MHC class I expression being largely C2TA independent 30 , expression of MHC class I genes was not affected in C2TAkd or Ciita -/-mice (Fig. 3c).…”

Section: Mtec-specific Silencing Of C2ta In Transgenic Micesupporting

confidence: 66%

“…Likewise, several MHC class II-unrelated and controversially discussed putative targets of C2TA 31 were expressed at identical levels in C2TAkd, Ciita -/-and wild-type mTECs (Fig. 3c), supporting the view that these genes may not at all or only indirectly be influenced by C2TA 30 . Collectively, these data established the faithful tissue-specificity, proper processing and functionality of the 'designer' miRNA transgene.…”

Section: Mtec-specific Silencing Of C2ta In Transgenic Micesupporting

confidence: 60%

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Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

et al. 2010

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Medullary thymic epithelial cells (mTECs) serve an essential function in central tolerance through expressing peripheral tissue-antigens. These antigens may be transferred to and presented by dendritic cells. Therefore, it is unclear whether mTECs, besides being an 'antigen reservoir', also serve a mandatory function as antigen presenting cells. Here, we reduced major histocompatibility complex class II on mTECs through transgenic expression of a C2TA-specific 'designer miRNA'. This resulted in an enlarged polyclonal CD4 single-positive compartment and, among thymocytes specific for model-antigens expressed in mTECs, enhanced selection of regulatory T cells (T reg ) at the expense of deletion. Our data document an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4 T cell tolerance and support an avidity model of T reg development versus deletion.3

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“…3b). Consistent with MHC class I expression being largely C2TA independent 30 , expression of MHC class I genes was not affected in C2TAkd or Ciita -/-mice (Fig. 3c).…”

Section: Mtec-specific Silencing Of C2ta In Transgenic Micesupporting

confidence: 66%

Section: Mtec-specific Silencing Of C2ta In Transgenic Micesupporting

confidence: 60%

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

et al. 2010

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“…The results obtained here suggest that naturally occurring genetic variants of rat Mhc2ta studied in vivo under physiological conditions have limited effects on the VRA phenotype, except for MHC IIassociated transcripts. This conclusion is also supported by in vivo findings in the mouse using transgenic animals (26,27). In this context it is of interest that expression of MHC II is often used as a marker of microglial activation, although it can be dissociated from other markers of activation as judged from our results.…”

Section: Discussionsupporting

confidence: 83%

Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

Harnesk

Swanberg

Öckinger

et al. 2008

The Journal of Immunology

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Presentation of Ag bound to MHC class II (MHC II) molecules to CD4+ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVGav1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN-γ in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVGav1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-γ. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVGav1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVGav1 and PVGav1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.

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“…Whereas the mechanism by which CIITA activates MHC II transcription has been extensively studied, the mechanisms by which CIITA controls the transcription of other target genes remains controversial (61). It was postulated that CIITA might compete with transcription factors interacting with the universal co-activator CBP/p300 as a mechanism for its repression of the IL-4 transcription (25) and collagen type I transcription (2).…”

Section: Discussionmentioning

confidence: 99%

CIITA Mediates Interferon-γ Repression of Collagen Transcription through Phosphorylation-dependent Interactions with Co-repressor Molecules

Harton

Smith

2008

Journal of Biological Chemistry

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Previously, we have demonstrated that major histocompatibility class II trans-activator (CIITA) is crucial in mediating interferon-␥ (IFN-␥)-induced repression of collagen type I gene transcription. Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B. In vitro phosphorylation of CIITA by GSK3 relies on a casein kinase I site three amino acids C-terminal to the GSK3 site in CIITA. Both GSK3 and casein kinase I inhibitors alleviate collagen repression and disrupt IFN-␥-mediated recruitment of Sin3B and HDAC2 to the collagen start site. Therefore, we have identified the region within CIITA responsible for mediating IFN-␥-induced inhibition of collagen synthesis.Extracellular matrix plays a critical role in maintaining the homeostasis of the vertebrate organisms. Increases in collagen expression in various tissues, ranging from heart to skin, often give rise to pathological manifestations such as atherosclerosis, cirrhosis, fibrosis, and scleroderma. Therefore, investigations of collagen expression not only further the understanding of the molecular mechanisms underlying the aforementioned diseases but provide insights into potential therapeutics. Type I collagen, which consists of two ␣1 chains (␣1(I)) and one ␣2 chain (␣2(I)), is the most abundant member of the collagen family. Type I collagen is the major component of the extracellular matrix in bones, tendons, and ligaments. It is the major component of heterotypic collagen fibrils and includes ϳ84% of the collagen synthesized by fibroblasts and myofibroblasts.Diverse collagen structure and distribution combined with complex interactions with other components of the extracellular matrix make the regulation of collagen expression an extremely complicated, yet critical process. Although regulation of collagen expression occurs at multiple levels, including transcription, processing of RNA, translation, and post-translation, collagen type I gene expression is regulated primarily at the transcriptional level. One of the common key features of fibrotic/atherosclerotic diseases is the infiltration of immune cells after injury, which release cytokines, such as IFN-␥, 2 to challenge local cells that produce collagen. The research in our laboratory has focused on unveiling the molecular mechanisms whereby IFN-␥ represses collagen synthesis. The investigations over the past few years in our laboratory as well as in others' have led to the identification of class II transactivator (CIITA) as a crucial factor in mediating IFN-␥-induced repression of collagen production (1-4).CIITA was first cloned from patients with bare lymphocyte syndrome, a hereditary immunodeficiency with a complete absence of major histocompatibility compl...

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Revisiting the specificity of the MHC class II transactivator CIITA in vivo

Cited by 18 publications

References 30 publications

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

CIITA Mediates Interferon-γ Repression of Collagen Transcription through Phosphorylation-dependent Interactions with Co-repressor Molecules

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