Regulation of T cell receptor (TCR)   gene expression by CD3 complex signaling in immature thymocytes: Implications for TCR  allelic exclusion

Gene targeting studies have shown that T cell receptor (TCR)-β gene expression and recombination are inhibited after deletion of an enhancer (Eβ) located at the 3′ end of the ∼500-kb TCR-β locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-β locus, the effects of Eβ deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, Eβ contributes to major chromatin remodeling directed to an ∼25-kb upstream domain comprised of the Dβ-Jβ locus regions. Accordingly, treatment of Eβ-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-β gene expression and promoted recombination within the Dβ-Jβ loci. Unexpectedly, however, epigenetic processes at distal Vβ genes on the 5′ side of the locus and at the 3′ proximal Vβ14 gene appear to be less dependent on Eβ, suggesting that Eβ activity is confined to a discrete region of the TCR-β locus. These findings have implications with respect to the developmental control of TCR-β gene recombination, and the process of allelic exclusion at this locus.

Download Full-text

A dynamical model of TCRβ gene recombination: Coupling the initiation of Dβ-Jβ rearrangement to TCRβ allelic exclusion

10.1101/200444 ◽

2017 ◽

Author(s):

Sébastien Jaeger ◽

Ricardo Lima ◽

Arnaud Meyroneinc ◽

Marie Bonnet ◽

Edgardo Ugalde ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Receptor ◽

Biological System ◽

Cell Receptor ◽

Allelic Exclusion ◽

Dna Rearrangement ◽

Gene Recombination

AbstractOne paradigm of random monoallelic gene expression is that of T-cell receptor (TCR)β allelic exclusion in T lymphocytes. However, the dynamics that sustain asymmetric choice in TCRβ dual allele usage and the production of TCRβ monoallelic expressing T-cells remain poorly understood. Here, we develop a computational model to explore a scheme of TCRβ allelic exclusion based on the stochastic initiation of DNA rearrangement [V(D)J recombination] at homologous alleles in T-cell progenitors, and thus account for the genotypic profiles typically associated with allelic exclusion in differentiated T-cells. Disturbances in these dynamics at the level of an individual allele have limited consequences on these pro1les, robust feature of the system that is underscored by our simulations. Our study predicts a biological system in which locus-specific, prime epigenetic allelic activation effects set the stage to both optimize the production of TCRβ allelically excluded T-cells and curtail the emergence of their allelically included counterparts.

Download Full-text

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

Molecular and Cellular Biology ◽

10.1128/mcb.13.9.5691-5701.1993 ◽

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.

Download Full-text

Crucial function of the pre-T-cell receptor (TCR) in TCRP selection, TCRbeta allelic exclusion and alphabeta versus gammadelta lineage commitment

Immunological Reviews ◽

10.1111/j.1600-065x.1998.tb01234.x ◽

1998 ◽

Vol 165 (1) ◽

pp. 111-119 ◽

Cited By ~ 86

Author(s):

Harald Boehmer ◽

Iannis Aifantis ◽

Orly Azogui ◽

Jacqueline Feinberg ◽

Claude Saint-Ruf ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Lineage Commitment ◽

Allelic Exclusion

Download Full-text

Analysis of immunoglobulin and T-cell receptor gene deficiency in graft rejection by gene expression profiles1

Transplantation Journal ◽

10.1097/01.tp.0000113803.45613.f8 ◽

2004 ◽

Vol 77 (4) ◽

pp. 580-586 ◽

Cited By ~ 4

Author(s):

Rachel A. DeFina ◽

Yurong Liang ◽

Hongzhen He ◽

Kathleen J. Haley ◽

Kenneth Christopher ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

T Cell Receptor ◽

Graft Rejection ◽

Receptor Gene ◽

Cell Receptor ◽

Gene Deficiency ◽

T Cell Receptor Gene ◽

Cell Receptor Gene

Download Full-text

RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease

Clinical Infectious Diseases ◽

10.1093/cid/ciw767 ◽

2017 ◽

Vol 64 (4) ◽

pp. 476-481 ◽

Cited By ~ 9

Author(s):

Jerome Bouquet ◽

Jennifer L. Gardy ◽

Scott Brown ◽

Jacob Pfeil ◽

Ruth R. Miller ◽

...

Keyword(s):

Gene Expression ◽

Chronic Disease ◽

T Cell ◽

B Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Rna Seq ◽

Viral Pathogen ◽

Complex Chronic Disease

Download Full-text

Identification and functional characterization of the human T-cell receptor beta gene transcriptional enhancer: common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor alpha and beta genes

Molecular and Cellular Biology ◽

10.1128/mcb.10.10.5486-5495.1990 ◽

1990 ◽

Vol 10 (10) ◽

pp. 5486-5495

Author(s):

L R Gottschalk ◽

J M Leiden

Keyword(s):

Gene Expression ◽

T Cell ◽

T Cell Receptor ◽

Binding Sites ◽

Cell Receptor ◽

Nuclear Proteins ◽

Transcriptional Enhancer ◽

Enhancer Element ◽

Beta 2 ◽

Beta Gene

A transcriptional enhancer has been mapped to a region 5.5 kilobases 3' of the C beta 2 gene in the human T-cell receptor (TCR) beta-chain locus. Transient transfections allowed localization of enhancer activity to a 480-base-pair HincII-XbaI restriction enzyme fragment. The TCR beta enhancer was active on both the minimal simian virus 40 promoter and a TCR beta variable gene promoter in both TCR alpha/beta + and TCR gamma/delta + T cells. It displayed significantly less activity in Epstein-Barr virus-transformed B cells and K562 chronic myelogenous leukemia cells and no activity in HeLa fibroblasts. DNA sequence analysis revealed that the enhancer contains a consensus immunoglobulin kappa E2 motif, as well as an AP-1-binding site and a cyclic AMP response element. DNase I footprint analyses using Jurkat T-cell nuclear extracts allowed the identification of five nuclear protein-binding sites, T beta 1 to T beta 5, within the enhancer element. Deletion and in vitro mutagenesis studies demonstrated that the T beta 2- and T beta 3- and T beta 4-binding sites are each required for full transcriptional enhancer activity. In contrast, deletion of the T beta 1- and T beta 5-binding sites had essentially no effect on enhancer function. Electrophoretic mobility shift assays demonstrated that TCR alpha/beta + and TCR gamma/delta + T cells expressed T beta 2-, T beta 3-, and T beta 4-binding activities. In contrast, non-T-cell lines, in which the enhancer was inactive, each lacked expression of at least one of these binding activities. TCR alpha and beta gene expression may be regulated by a common set of T-cell nuclear proteins in that the T beta 2 element binding a set of cyclic AMP response element-binding proteins that are also bound by the T alpha 1 element of the human TCR alpha enhancer and the decamer element present in a large number of human and murine TCR beta promoters. Similarly, the T beta 5 TCR beta-enhancer element and the T alpha 2 TCR alpha-enhancer element bind at least one common T-cell nuclear protein. Taken together, these results suggest that TCR beta gene expression is regulated by the interaction of multiple T cell nuclear proteins with a transcriptional enhancer element located 3' of the C beta 2 gene and that some of these proteins may be involved in the coordinate regulation of TCR alpha and beta gene expression.

Download Full-text