scholarly journals New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling

2005 ◽  
Vol 201 (11) ◽  
pp. 1715-1723 ◽  
Author(s):  
Willem A. Dik ◽  
Karin Pike-Overzet ◽  
Floor Weerkamp ◽  
Dick de Ridder ◽  
Edwin F.E. de Haas ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Gene Expression Profiling ◽  
T Cell Receptor ◽  
Expression Profiling ◽  
Gene Rearrangement ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Human T Cell

To gain more insight into initiation and regulation of T cell receptor (TCR) gene rearrangement during human T cell development, we analyzed TCR gene rearrangements by quantitative PCR analysis in nine consecutive T cell developmental stages, including CD34+ lin− cord blood cells as a reference. The same stages were used for gene expression profiling using DNA microarrays. We show that TCR loci rearrange in a highly ordered way (TCRD-TCRG-TCRB-TCRA) and that the initiating Dδ2-Dδ3 rearrangement occurs at the most immature CD34+CD38−CD1a− stage. TCRB rearrangement starts at the CD34+CD38+CD1a− stage and complete in-frame TCRB rearrangements were first detected in the immature single positive stage. TCRB rearrangement data together with the PTCRA (pTα) expression pattern show that human TCRβ-selection occurs at the CD34+CD38+CD1a+ stage. By combining the TCR rearrangement data with gene expression data, we identified candidate factors for the initiation/regulation of TCR recombination. Our data demonstrate that a number of key events occur earlier than assumed previously; therefore, human T cell development is much more similar to murine T cell development than reported before.

scholarly journals Early T Cell Receptor β Gene Expression Is Regulated by the Pre-T Cell Receptor–CD3 Complex

1999 ◽  
Vol 190 (1) ◽  
pp. 141-144 ◽  
Author(s):  
Iannis Aifantis ◽  
Jacqueline Feinberg ◽  
Hans Jörg Fehling ◽  
James P. Di Santo ◽  
Harald von Boehmer
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Mutant Mice ◽  
Dependent Signal

We have examined the question of whether there is an additional checkpoint in T cell development that regulates T cell receptor (TCR)-β expression in CD25+44− thymocytes by mechanisms that are independent of the pre-TCR. Our analysis in various mutant mice indicates that all changes in cytoplasmic TCR-β expression can be accounted for by pre-TCR–dependent signal mediation, putting into question the function of a putative pro-TCR.

scholarly journals Enhancer-dependent and -independent steps in the rearrangement of a human T cell receptor delta transgene.

1994 ◽  
Vol 179 (1) ◽  
pp. 43-55 ◽  
Author(s):  
P Lauzurica ◽  
M S Krangel
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Gamma Delta ◽  
Delta Gene ◽  
Alpha Beta

The rearrangement and expression of T cell receptor (TCR) gene segments occurs in a highly ordered fashion during thymic ontogeny of T lymphocytes. To study the regulation of gene rearrangement within the TCR alpha/delta locus, we generated transgenic mice that carry a germline human TCR delta minilocus that includes V delta 1, V delta 2, D delta 3, J delta 1, J delta 3, and C delta segments, and either contains or lacks the TCR delta enhancer. We found that the enhancer-positive construct rearranges stepwise, first V to D, and then V-D to J. Construct V-D rearrangement mimics a unique property of the endogenous TCR delta locus. V-D-J rearrangement is T cell specific, but is equivalent in alpha/beta and gamma/delta T lymphocytes. Thus, either there is no commitment to the alpha/beta and gamma/delta T cell lineages before TCR delta gene rearrangement, or if precommitment occurs, it does not operate directly on TCR delta gene cis-acting regulatory elements to control TCR delta gene rearrangement. Enhancer-negative mice display normal V to D rearrangement, but not V-D to J rearrangement. Thus, the V-D to J step is controlled by the enhancer, but the V to D step is controlled by separate elements. The enhancer apparently controls access to J delta 1 but not D delta 3, suggesting that a boundary between two independently regulated domains of the minilocus lies between these elements. Within the endogenous TCR alpha/delta locus, this boundary may represent the 5' end of a chromatin regulatory domain that is opened by the TCR delta enhancer during T cell development. The position of this boundary may explain the unique propensity of the TCR delta locus to undergo early V to D rearrangement. Our results indicate that the TCR delta enhancer performs a crucial targeting function to regulate TCR delta gene rearrangement during T cell development.

scholarly journals T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production.

1995 ◽  
Vol 182 (1) ◽  
pp. 121-127 ◽  
Author(s):  
H T Petrie ◽  
F Livak ◽  
D Burtrum ◽  
S Mazel
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
High Price ◽  
Beta Chain ◽  
Cell Production

The antigen-specific receptors of T and B lymphocytes are generated by somatic recombination between noncontiguous gene segments encoding the variable portions of these molecules. The semirandom nature of this process, while desirable for the generation of diversity, has been thought to exact a high price in terms of sterile (out-of-frame) products. Historically, the majority of T lymphocytes generated in mammals were thought to be useless, either because they generated such sterile rearrangements or because the receptors generated did not appropriately recognize self-molecules (i.e., positive and negative selection). In the studies described here, we characterize the onset of T cell receptor (TCR) alpha and beta chain gene rearrangements and quantitate their progression throughout T cell development. The results show that T cell production efficiency is enhanced through (a) rearrangement of TCR-beta chain genes early during T cell development, with selective expansion of those cells possessing in-frame rearrangements; (b) deletion of sterile rearrangements at the TCR-alpha chain locus through ordered (proximal to distal) sequential recombination; and (c) modification of nonselectable alpha/beta heterodimer specificities through generation and expression of new TCR-alpha chains. In addition, we demonstrate strict correlations between successful TCR-beta gene rearrangement, the onset of TCR-alpha gene rearrangement, rapid cell division, and programmed cell death, which together serve to maintain cell turnover and homeostasis during T cell development.

scholarly journals Regulation of T-cell receptor gene expression in human T-cell development.

1985 ◽  
Vol 82 (13) ◽  
pp. 4503-4507 ◽  
Author(s):  
M. K. Collins ◽  
G. Tanigawa ◽  
A. M. Kissonerghis ◽  
M. Ritter ◽  
K. M. Price ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
T Cell Development ◽  
Cell Receptor ◽  
Human T Cell ◽  
T Cell Receptor Gene ◽  
Receptor Gene Expression ◽  
Cell Receptor Gene

scholarly journals Identifying low-grade cellular rejection after heart transplantation in children by using gene expression profiling

2018 ◽  
Vol 50 (3) ◽  
pp. 190-196 ◽  
Author(s):  
Annie Xin ◽  
Melissa G. Y. Lee ◽  
Yifang Hu ◽  
Vera Ignjatovic ◽  
William Y. Shi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Heart Transplantation ◽  
Gene Expression Profiling ◽  
T Cell Receptor ◽  
Expression Profiling ◽  
Gene Families ◽  
Cell Receptor ◽  
Low Grade ◽  
Immunoglobulin Gene

Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection after heart transplantation but is costly and invasive. This study aims to distinguish no rejection (0R) from low-grade rejection (1R/2R) after heart transplantation in children by using global gene expression profiling in blood. A total of 106 blood samples with corresponding EMB from 18 children who underwent heart transplantation from 2011 to 2014 were analyzed (18 baseline/pretransplantation samples, 88 EMB samples). Corresponding rejection grades for each blood sample were 0R in 39% (34/88), 1R in 51% (45/88), and 2R in 10% (9/88). mRNA from each sample was sequenced. Differential expression analysis was performed at the gene level. A k-nearest neighbor (kNN) analysis was applied to the most differentially expressed (DE) genes to identify rejection after transplantation. Mean age at transplantation was 10.0 ± 5.4 yr. Expression of B cell and T cell receptor sequences was used to measure the effect of posttransplantation immunosuppression. Follow-up samples had lower levels of immunoglobulin gene families compared with pretransplantation ( P < 3E-5) (lower numbers of activated B cells). T cell receptor alpha and beta gene families had decreased expression in 0R samples compared with pretransplantation ( P < 4E-5) but recovered to near baseline levels in 1R/2R samples. kNN using the most DE gene (MKS1) and k = 9 nearest neighbors correctly identified 83% (73/88) of 1R/2R compared with 0R by leave-one-out cross validation. Using a genomic approach we can distinguish low-grade cellular allograft rejection (1R/2R) from no rejection (0R) after heart transplantation in children despite a wide age range.

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.

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