Early Growth Response Transcription Factors Are Required for Development of CD4−CD8− Thymocytes to the CD4+CD8+ Stage

Carleton, Michael; Haks, Mariëlle C.; Smeele, Sigrid A. A.; Jones, Allan R.; Belkowski, Stanley M.; Berger, Marc A.; Linsley, Peter S.; Kruisbeek, Ada M.; Wiest, David L.

doi:10.4049/jimmunol.168.4.1649

Cited by 83 publications

(105 citation statements)

References 58 publications

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“…EGR1 was also represented by two probesets and the expression levels were significantly reduced after 16 h. This gene codes for a zinc-finger transcription factor. EGR proteins play central roles in controlling the differentiation program initiated by pre-TCR signalling [37,38] and in mature CD4 + T cells it was recently shown that EGR1 is required for CD154 (CD40 ligand) transcription [39]. The transcriptional regulators HEY1 and KLF10 are involved in regulation of cell fate decisions and proliferation, respectively, but have yet not been investigated in T lineage cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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“…Most of the DN cells expressed CD3 at a moderate or low level, although a CD3 Ϫ population was also identified which are likely to be even more immature. CD3 ϩ DN cells are likely to be either immature T cells or CD3 ϩ NK cells, while DP cells could represent a slightly later stage of immature T cell development (23). However, some DP cells, proposed to be activated T cells, are normally present in adults and are increased in adults with various autoimmune disorders (24,25).…”

Section: Discussionmentioning

confidence: 99%

Intestinal αβ T Cells Differentiate and Rearrange Antigen Receptor Genes In Situ in the Human Infant

Williams

Bland

Phillips

et al. 2004

The Journal of Immunology

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Intestinal Ag exposure during neonatal life influences appropriate adult immune responses. To define the mechanisms shaping the T cell repertoire during this period, we examined T cell differentiation and receptor diversity in the intestine of human infants. Developmental phenotypes of intraepithelial and lamina propria intestinal T cells from infants aged 1 day to 2 years were assessed ex vivo by flow cytometry and in situ by triple-fluorescent immunohistochemistry. Gene recombination-specific enzymes were assessed by PCR. TCR β-chain V region gene diversity was determined by sequencing. Several different early lineage T cell populations were present neonatally: CD3+4−8− T cells were present at birth and numbers decreased during the neonatal period; CD3+4+8+ T cells were present in low numbers throughout infancy; and CD3+4+8− or CD3+4−8+ T cells increased with age. Very early lineage T cells, CD3−2−7+ and CD3−2+7+, were present neonatally, but were essentially absent at 1 year. Most lamina propria T cells differentiated rapidly after birth, but maturation of intraepithelial T cells took place over 1 year. Intestinal samples from infants less than 6 mo old contained transcripts of T early α and TdT, and 15 of 19 infant samples contained mRNA for RAG-1, some coexpressing RAG-2. TCR β-chain repertoires were polyclonal in infants. Immature T cells, pre-T cells, and genes involved in T cell recombination were found in the intestine during infancy. T cell differentiation occurs within the neonatal human intestine, and the TCR repertoire of these developing immature T cells is likely to be influenced by luminal Ags. Thus, mucosal T cell responsiveness to environmental Ag is shaped in situ during early life.

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“…We have shown that Egr-1 is also induced in T cells upon activation with PMA and IO. The role of Egr1 in T cells is less well defined; however, it has been suggested to act as a regulator of Fas ligand expression (49) and thymocyte development (50). Significantly, the Egr1 promoter is activated by T cell receptor agonist ligands (51), and Egr1 gene expression increases shortly after concanavalin-A stimulation of cultured T lymphocytes (52), observations that support a potential role for Egr1-mediated transcription of genes in activated T cells.…”

Section: Figmentioning

confidence: 99%

Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Mestre

Khachigian

Santiago

et al. 2003

Journal of Biological Chemistry

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Cleavage of heparan sulfate by the ␤-D-endoglucuronidase heparanase (HPSE) is a fundamental event in a number of important physiological processes including inflammation, wound healing, and angiogenesis. HPSE activity has also been directly correlated with pathological conditions such as tumor growth and metastasis and autoimmune disease. The tight regulation of HPSE expression and function is critical to ensure homeostasis of the normal physiological processes to which it contributes and to prevent imbalance toward pathological situations. Little is known about the transcriptional mechanisms that regulate HPSE expression. In this study we have shown human HPSE gene transcription in Jurkat T cells is induced upon activation. Functional analysis of the HPSE promoter has identified a 280-bp region that is highly inducible. Mutation studies together with supershift experiments have identified a 4-bp motif that binds the transcription factor early growth response-1 (Egr1) and is critical in regulating inducible HPSE gene transcription. Furthermore, the overexpression of Egr1 resulted in the enhanced activation of the HPSE promoter. By using MAPK pathway inhibitors, we have also shown that inducible expression of HPSE mRNA and the activity of the 280-bp HPSE promoter element are dependent on the ERK1/2 (MEK1/2) pathway. This pathway is critical for induction of Egr1 expression at both the mRNA and protein level in T cells, an observation that provides further support to Egr1 playing an important role as a key activator of HPSE expression. In addition, HPSE and Egr1 were shown to co-localize by immunohistochemistry to invading mononuclear leukocytes in actively induced experimental autoimmune encephalomyelitis in rats. These findings provide the first insight into the mechanisms controlling inducible transcription of the HPSE gene, and could represent an important lead into understanding how HPSE expression is deregulated in metastatic tumor cells.Heparan sulfate proteoglycans are key structural components of the extracellular matrix (ECM) 1 and cell surfaces. They comprise a protein core covalently linked to linear chains of the complex sulfated glycosaminoglycan, heparan sulfate (HS) (1-3). The HS side chains of heparan sulfate proteoglycans mediate the assembly and stability of the ECM through interactions with the various matrix components (e.g. collagen, laminin, and fibronectin) (1, 3) and also specifically bind a range of cytokines and growth factors (e.g. basic fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, and transforming growth factor-␤) thereby functioning as a storage depot for these factors (4, 5). The ␤-D-endoglycosidase heparanase (HPSE) cleaves HS and facilitates the degradation of the ECM and the release of HS-bound growth factors (6, 7). Heparanase is a normal constituent of activated leukocytes, endothelial cells, vascular smooth muscle cells, and cytotrophoblasts; however, its expression is also "hijacked" by metastatic tumor cells (6, 7). The level of HPSE activit...

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Early Growth Response Transcription Factors Are Required for Development of CD4−CD8− Thymocytes to the CD4+CD8+ Stage

Cited by 83 publications

References 58 publications

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Intestinal αβ T Cells Differentiate and Rearrange Antigen Receptor Genes In Situ in the Human Infant

Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

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