scholarly journals CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation

2007 ◽  
Vol 204 (7) ◽  
pp. 1543-1551 ◽  
Author(s):  
Hyoung-Pyo Kim ◽  
Warren J. Leonard
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Receptor ◽  
Cpg Island ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Foxp3 Gene

Regulatory T cells (T reg cells) are a population of CD4+ T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor–responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and FoxP3 expression. Interestingly, transforming growth factor-β, which induces T reg cell formation, decreases methylation of the CpG island and increases FoxP3 expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces FoxP3 expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor–induced FoxP3 expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island.

scholarly journals The ht beta gene encodes a novel CACCC box-binding protein that regulates T-cell receptor gene expression

1993 ◽  
Vol 13 (9) ◽  
pp. 5691-5701
Author(s):  
Y Wang ◽  
J A Kobori ◽  
L Hood
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Binding Protein ◽  
Cell Receptor ◽  
Regulatory Function ◽  
Human T Cell ◽  
Alpha Gene ◽  
Beta Gene

A gene encoding a novel CACCC box-binding protein that binds to the promoter region of the human T-cell receptor (TCR) V beta 8.1 gene and the mouse TCR alpha gene silencer has been cloned. This gene, termed ht beta, contains four zinc fingers of the class Cys2-X12-His2 that may be responsible for DNA binding and a highly negatively charged region that defines a putative transcriptional activation domain. Analysis of the expression of ht beta mRNA revealed similar expression levels and patterns in various cell lines. The bacterially expressed ht beta protein can bind to the CACCC box in both the human TCR V beta 8.1 gene promoter and the mouse TCR alpha gene silencer. The CACCC box is essential for efficient transcription of the V beta 8.1 promoter. Cotransfection with an ht beta expression plasmid and a reporter vector indicated that ht beta can activate human TCR V beta 8.1 gene transcription. ht beta also is able to counteract the silencing effect of the mouse TCR alpha gene silencer. The CACCC box has been found in almost all V beta 8.1 gene subfamily members and in both TCR alpha and beta gene enhancers in humans and mice. These results suggest that the CACCC box-binding protein may have an important regulatory function for TCR gene expression in alpha beta T cells versus gamma delta T cells.

scholarly journals Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2839-2846 ◽  
Author(s):  
Svenja Steinfelder ◽  
Stefan Floess ◽  
Dirk Engelbert ◽  
Barbara Haeringer ◽  
Udo Baron ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Transcriptional Activity ◽  
Epigenetic Modification ◽  
Cell Receptor ◽  
Noncoding Region ◽  
Differentially Methylated Region

Abstract CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell priming with certain cytokines, but how its expression and stability are regulated at the molecular level is largely unknown. Here, we identified and characterized a noncoding region of the human CCR6 locus that displayed unmethylated CpG motifs (differentially methylated region [DMR]) selectively in CCR6+ lymphocytes. CCR6 expression on circulating CD4+ T cells was stable on cytokine-induced proliferation but partially down-regulated on T-cell receptor stimulation. However, CCR6 down-regulation was mostly transient, and the DMR within the CCR6 locus remained demethylated. Notably, in vitro induction of CCR6 expression with cytokines in T-cell receptor-activated naive CD4+ T cells was not associated with a demethylated DMR and resulted in unstable CCR6 expression. Conversely, treatment with the DNA methylation inhibitor 5′-azacytidine induced demethylation of the DMR and led to increased and stable CCR6 expression. Finally, when cloned into a reporter gene plasmid, the DMR displayed transcriptional activity in memory T cells that was suppressed by DNA methylation. In summary, we have identified a noncoding region of the human CCR6 gene with methylation-sensitive transcriptional activity in CCR6+ T cells that controls stable CCR6 expression via epigenetic mechanisms.

scholarly journals Phosphoinositide 3-Kinase Regulation of T Cell Receptor-mediated Interleukin-2 Gene Expression in Normal T Cells

1998 ◽  
Vol 273 (43) ◽  
pp. 28025-28031 ◽  
Author(s):  
Astrid M. Eder ◽  
Lourdes Dominguez ◽  
Thomas F. Franke ◽  
Jonathan D. Ashwell
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Kinase Regulation ◽  
Phosphoinositide 3 Kinase

Acquisition of FOXP3 Expression by Human Effector CD4+ T Cells Is a Natural Consequence of Antigen Recognition.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 870-870
Author(s):  
J. Joseph Melenhorst ◽  
Phillip Scheinberg ◽  
David R. Ambrozak ◽  
Nancy F. Hensel ◽  
Daniel C. Douek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Antigen Recognition ◽  
Natural Consequence ◽  
Antigen Stimulation ◽  
Hla Dr

Abstract Recent data suggest that CD4+CD25+FOXP3+ regulatory T cells (TR) can be generated from CD4+CD25−FOXP3− T cells in the periphery. We studied the induction of CD4+CD25+FOXP3+ T cells during the course of immune responses to cytomegalovirus, tetanus toxoid, purified protein derivative and streptokinase. Peripheral blood mononuclear cells (PBMC) from healthy donors were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFDA) and stimulated with antigen for 6–7 days. Cells were stained for CD3, CD4, CD25, HLA-DR, CD38, and intracellular FOXP3. Responders to antigens had proliferating (CFDA[dim]) CD4+ T cells expressing CD25 and the activation markers CD38 and HLA-DR. In PBMC from five donors, a median of 37% (range 9–57%) of the proliferating fraction expressed FOXP3 (figure) which mostly co-expressed CD25, HLA-DR and CD38, suggesting that FOXP3 expression is the consequence of cellular activation triggered through the T cell receptor. Since all of these healthy subjects had circulating, pre-existing CD4+CD25+FOXP3+ T cells in the absence of ex vivo antigen stimulation, however, it was possible that these gave rise to the FOXP3+ responder cells. Antigen stimulation of PBMC from three donors aged 69–70 years with no detectable CD4+CD25+FOXP3+ T cells also induced proliferating activated CD4+CD25+FOXP3+ T cells, excluding the possibility that a pre-existing pool of FOXP3+ T cells gave rise to this population. Subsequently, we sorted CD4+ T cells that proliferated in response to antigen by flow cytometry on the basis of FOXP3 expression to sequence the T cell receptor-β CDR3 regions and to establish the T cell clonotype structure of proliferating FOXP3-positive and -negative T cells. These data also indicate that effector CD4+ T cells acquire FOXP3 expression during the course of an immune response. Based on these and previously reported findings, we propose that the acquisition of FOXP3 expression by effector CD4+ T cells is a natural consequence of antigen recognition that serves as a specific regulatory feedback system. Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering

scholarly journals The ht beta gene encodes a novel CACCC box-binding protein that regulates T-cell receptor gene expression.

1993 ◽  
Vol 13 (9) ◽  
pp. 5691-5701 ◽  
Author(s):  
Y Wang ◽  
J A Kobori ◽  
L Hood
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Binding Protein ◽  
Cell Receptor ◽  
Regulatory Function ◽  
Human T Cell ◽  
Alpha Gene ◽  
Beta Gene

A gene encoding a novel CACCC box-binding protein that binds to the promoter region of the human T-cell receptor (TCR) V beta 8.1 gene and the mouse TCR alpha gene silencer has been cloned. This gene, termed ht beta, contains four zinc fingers of the class Cys2-X12-His2 that may be responsible for DNA binding and a highly negatively charged region that defines a putative transcriptional activation domain. Analysis of the expression of ht beta mRNA revealed similar expression levels and patterns in various cell lines. The bacterially expressed ht beta protein can bind to the CACCC box in both the human TCR V beta 8.1 gene promoter and the mouse TCR alpha gene silencer. The CACCC box is essential for efficient transcription of the V beta 8.1 promoter. Cotransfection with an ht beta expression plasmid and a reporter vector indicated that ht beta can activate human TCR V beta 8.1 gene transcription. ht beta also is able to counteract the silencing effect of the mouse TCR alpha gene silencer. The CACCC box has been found in almost all V beta 8.1 gene subfamily members and in both TCR alpha and beta gene enhancers in humans and mice. These results suggest that the CACCC box-binding protein may have an important regulatory function for TCR gene expression in alpha beta T cells versus gamma delta T cells.

scholarly journals Identification of a Late Stage of Small Noncycling pTα−  Pre-T Cells as Immediate Precursors of T Cell Receptor α/β+  Thymocytes

1998 ◽  
Vol 188 (8) ◽  
pp. 1401-1412 ◽  
Author(s):  
César Trigueros ◽  
Almudena R. Ramiro ◽  
Yolanda R. Carrasco ◽  
Virginia G. de Yebenes ◽  
Juan P. Albar ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Developmental Model ◽  
Developmental Expression ◽  
Thymocyte Development ◽  
Cell Stage

During thymocyte development, progression from T cell receptor (TCR)β to TCRα rearrangement is mediated by a CD3-associated pre-TCR composed of the TCRβ chain paired with pre-TCRα (pTα). A major issue is how surface expression of the pre-TCR is regulated during normal thymocyte development to control transition through this checkpoint. Here, we show that developmental expression of pTα is time- and stage-specific, and is confined in vivo to a limited subset of large cycling human pre-T cells that coexpress low density CD3. This restricted expression pattern allowed the identification of a novel subset of small CD3− thymocytes lacking surface pTα, but expressing cytoplasmic TCRβ, that represent late noncycling pre-T cells in which recombination activating gene reexpression and downregulation of T early α transcription are coincident events associated with cell cycle arrest, and immediately preceding TCRα gene expression. Importantly, thymocytes at this late pre-T cell stage are shown to be functional intermediates between large pTα+ pre-T cells and TCRα/β+ thymocytes. The results support a developmental model in which pre-TCR–expressing pre-T cells are brought into cycle, rapidly downregulate surface pre-TCR, and finally become small resting pre-T cells, before the onset of TCRα gene expression.

Molecular analysis of T cell receptor gamma gene expression in allo-activated splenic T cells of adult mice

1988 ◽  
Vol 18 (12) ◽  
pp. 1907-1915 ◽  
Author(s):  
Barry Jones ◽  
Simon Carding ◽  
Susan Kyes ◽  
Shelley Mjolsness ◽  
Charles Janeway ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Molecular Analysis ◽  
Cell Receptor ◽  
Adult Mice
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