Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells

Waldburger, Jean Marc; Rossi, Simona W.; Holländer, Georg A.; Rodewald, Hans Reimer; Reith, Walter; Acha‐Orbea, Hans

doi:10.1182/blood-2002-06-1855

Cited by 34 publications

(38 citation statements)

References 86 publications

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“…Mice lacking C2ta pIV and p(III+IV) have been described [18,19,37]. The generation of mice carrying a targeted mutation of pI will be described elsewhere (LeibundGut-Landmann et al, manuscript in preparation).…”

Section: Methodsmentioning

confidence: 99%

Circulating, soluble forms of major histocompatability complex antigens are not exosome‐associated

et al. 2006

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In vitro studies have shown that soluble MHC (sMHC) released by cell lines is bound to nano-vesicles termed exosomes. It is thought that exosomes may represent the major reservoir of sMHC class I and II molecules in biological fluids. However, most studies have been confined to in vitro assays performed with cell lines. We show here that sMHC in the serum or plasma differs from exosome-bound sMHC in five ways: In contrast to exosome-associated sMHC, circulating sMHC is of low density, has a low apparent molecular mass (40-300 kDa) and is not detergent-labile. Moreover, the majority of MHC class II isoforms and MHC class I in blood are not physically linked and circulating HLA-DR is accessible to an antibody specific for the HLA-DR a-chain intracellular epitope, which is masked by its association with cellular or exosomal membranes. Finally, utilizing transcriptional activator of murine MHC class II (C2ta) promotermutant mice, we showed that the release of sMHC class II into the circulation is dependent on the C2ta pI promoter, but not pIII or pIV. This suggests that myeloid dendritic cells and/or macrophages, which preferentially use promoter pI of the C2ta gene, produce most of the sMHC class II found in the circulation.

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Section: Methodsmentioning

confidence: 99%

Circulating, soluble forms of major histocompatability complex antigens are not exosome‐associated

et al. 2006

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“…Thus pIV is absolutely essential for constitutive expression of CIITA in cTEC. It is also required in mTEC [50]. The molecular mechanism mediating pIV activation in TEC is not known.…”

Section: Tecmentioning

confidence: 99%

“…Unexpectedly, cTEC of pIV knockout mice are MHCII - [40,50]. This loss of MHCII expression results in the abrogation of positive selection of CD4 + T cells in the thymus [40,50].…”

Section: Tecmentioning

confidence: 99%

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

et al. 2004

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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.

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“…Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J) were obtained from The Jackson Laboratory and maintained as a homozygous and heterozygous colony, respectively. The CIITA lox/lox (CIIta tm1Wrth ), generated and provided by Dr. W. Reith (University of Geneva, Geneva, Switzerland) and the Ctnnb1 lox/lox(ex3) mice have previously been reported (27,28) and were kept as homozygotes. Because a robust activation of the canonical Wnt signaling pathway in these mice is already achieved by a single transgene (27), all our experiments were conducted using mice compound heterozygous for the exon 3 deletion of the ␤-catenin gene.…”

Section: Micementioning

confidence: 99%

Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

Žuklys

Gill

Keller

et al. 2009

The Journal of Immunology

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Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation of the canonical Wnt signaling pathway by a stabilizing mutation of β-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function.

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Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells

Cited by 34 publications

References 86 publications

Circulating, soluble forms of major histocompatability complex antigens are not exosome‐associated

Circulating, soluble forms of major histocompatability complex antigens are not exosome‐associated

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

Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

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