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 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 Temporal and lineage-specific control of T cell receptor alpha/delta gene rearrangement by T cell receptor alpha and delta enhancers.

1994 ◽  
Vol 179 (6) ◽  
pp. 1913-1921 ◽  
Author(s):  
P Lauzurica ◽  
M S Krangel
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
Cell Subset ◽  
Cell Receptor ◽  
Receptor Alpha ◽  
Specific Step ◽  
Delta Gene ◽  
Alpha Beta ◽  
Cell Receptor Alpha

To analyze the regulation of gene rearrangement at the T cell receptor (TCR) alpha/delta locus during T cell development, we generated transgenic mice carrying a human TCR delta gene minilocus. We previously showed that the presence of the TCR delta enhancer (E delta) within the J delta 3-C delta intron was required to activate a specific step (V-D to J) of transgene rearrangement, and that rearrangement was activated equivalently in the precursors of alpha beta and gamma delta T cells. To further explore the role of transcriptional enhancers in establishing the developmental pattern of gene rearrangement at the TCR alpha/delta locus, we substituted the TCR alpha enhancer (E alpha) in place of E delta within the transgenic minilocus. We found that V-D-J rearrangement of the E alpha+ minilocus was restricted to the alpha beta T cell subset. Further, we found that although V-D-J rearrangement of the E delta+ minilocus was initiated in the fetal thymus by day 14.5, V-D-J rearrangement of the E alpha+ minilocus did not occur until fetal day 16.5. Finally, whereas V-D-J rearrangement of the E delta+ minilocus is essentially completed within the triple negative population of postnatal thymocytes, V-D-J rearrangement of the E alpha+ minilocus is only initiated late within this population. Since the properties of minilocus rearrangement under the control of E delta and E alpha parallel the properties of V delta-D delta-J delta and V alpha-J alpha rearrangement at the endogenous TCR alpha/delta locus, we conclude that these enhancers play an important role in orchestrating the developmental program of rearrangements at this locus.

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 Rearrangement and expression of T-cell receptor delta genes in T-cell acute lymphoblastic leukemias

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 334-342
Author(s):  
JJ van Dongen ◽  
IL Wolvers-Tettero ◽  
F Wassenaar ◽  
J Borst ◽  
P van den Elsen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Receptor Expression ◽  
The Other ◽  
Gamma Delta ◽  
Delta Gene ◽  
Gene Transcripts ◽  
Alpha Beta

We have analyzed T-cell receptor delta (TcR-delta) gene rearrangement and transcription in appropriately phenotyped mononuclear cells derived from 12 patients with T-cell acute lymphoblastic leukemia (T-ALL). The T-ALL cells were also analyzed for rearrangement and transcription of the T-cell receptor(TcR)-beta and gamma genes as well as for the presence of TcR-alpha gene transcripts. Four T-ALLs expressed TcR-gamma delta at the cell surface, while three expressed TcR-alpha beta. The other five T-ALLs did not express a TcR-CD3 complex on their cell membrane. The TcR-gamma delta + T-ALL had rearranged both TcR-delta gene alleles and contained mature 2.2 and 1.5 kb TcR-delta transcripts. In one case, immature 1.9 and 1.2 kb TcR-delta transcripts were also found. Furthermore they contained mature TcR-gamma mRNA, mature or immature TcR-beta mRNA, but no TcR-alpha mRNA. The three TcR-alpha beta + T-ALLs contained mature alpha and beta transcripts, but lacked TcR- delta transcripts as a result of deletion of both TcR-delta gene alleles. These data are in line with a mutually exclusive expression of TcR-alpha and -delta genes, which may be important to ensure the presence of only one type of TcR per T cell. One of the five CD3- T- ALLs had germline TcR-beta, gamma, and delta genes. The other four CD3- T-ALLs had rearranged their TcR-beta, gamma, and delta genes and contained immature 1.9 and 1.2 kb TcR-delta gene transcripts. Remarkably, one of these T-ALLs also contained TcR-alpha transcripts in addition to the immature TcR-delta transcripts, which was in line with the deletion of one TcR-delta gene allele and rearrangement of the other allele. This suggests that prevention of dual receptor expression may not only be regulated by the presence of germline TcR-alpha genes in TcR-gamma delta + cells or by deletion of both TcR-delta gene alleles in TcR-alpha beta + cells, but also via other regulation mechanisms. Finally, our data indicated that the combinatorial repertoire of the TcR-delta genes is limited, which has also been described for the TcR-gamma genes.

scholarly journals Rearrangement and expression of T-cell receptor delta genes in T-cell acute lymphoblastic leukemias

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 334-342 ◽  
Author(s):  
JJ van Dongen ◽  
IL Wolvers-Tettero ◽  
F Wassenaar ◽  
J Borst ◽  
P van den Elsen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Receptor Expression ◽  
The Other ◽  
Gamma Delta ◽  
Delta Gene ◽  
Gene Transcripts ◽  
Alpha Beta

Abstract We have analyzed T-cell receptor delta (TcR-delta) gene rearrangement and transcription in appropriately phenotyped mononuclear cells derived from 12 patients with T-cell acute lymphoblastic leukemia (T-ALL). The T-ALL cells were also analyzed for rearrangement and transcription of the T-cell receptor(TcR)-beta and gamma genes as well as for the presence of TcR-alpha gene transcripts. Four T-ALLs expressed TcR-gamma delta at the cell surface, while three expressed TcR-alpha beta. The other five T-ALLs did not express a TcR-CD3 complex on their cell membrane. The TcR-gamma delta + T-ALL had rearranged both TcR-delta gene alleles and contained mature 2.2 and 1.5 kb TcR-delta transcripts. In one case, immature 1.9 and 1.2 kb TcR-delta transcripts were also found. Furthermore they contained mature TcR-gamma mRNA, mature or immature TcR-beta mRNA, but no TcR-alpha mRNA. The three TcR-alpha beta + T-ALLs contained mature alpha and beta transcripts, but lacked TcR- delta transcripts as a result of deletion of both TcR-delta gene alleles. These data are in line with a mutually exclusive expression of TcR-alpha and -delta genes, which may be important to ensure the presence of only one type of TcR per T cell. One of the five CD3- T- ALLs had germline TcR-beta, gamma, and delta genes. The other four CD3- T-ALLs had rearranged their TcR-beta, gamma, and delta genes and contained immature 1.9 and 1.2 kb TcR-delta gene transcripts. Remarkably, one of these T-ALLs also contained TcR-alpha transcripts in addition to the immature TcR-delta transcripts, which was in line with the deletion of one TcR-delta gene allele and rearrangement of the other allele. This suggests that prevention of dual receptor expression may not only be regulated by the presence of germline TcR-alpha genes in TcR-gamma delta + cells or by deletion of both TcR-delta gene alleles in TcR-alpha beta + cells, but also via other regulation mechanisms. Finally, our data indicated that the combinatorial repertoire of the TcR-delta genes is limited, which has also been described for the TcR-gamma genes.

scholarly journals p53 prevents maturation to the CD4+CD8+ stage of thymocyte differentiation in the absence of T cell receptor rearrangement.

1996 ◽  
Vol 183 (4) ◽  
pp. 1923-1928 ◽  
Author(s):  
D Jiang ◽  
M J Lenardo ◽  
J C Zúñiga-Pflücker
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
T Cell Development ◽  
P53 Gene ◽  
Cell Receptor ◽  
Cell Development ◽  
Beta Chain ◽  
Thymocyte Development ◽  
B And T Lymphocytes

Rearrangement of the immunoglobulin (Ig) and T cell receptor (TCR) gene loci allows for the generation of B and T lymphocytes with antigen-specific receptors. Complete rearrangement and expression of the TCR-beta chain enables immature thymocytes to differentiate from the CD4-CD8- to the CD4+CD8+ stage mice in which rearrangement is impaired, such as severe combined immunodeficient (SCID) mice or recombinase activating gene-deficient (RAG-/-) mice, lack mature B and T lymphocytes. Thymocytes from these mice are arrested at the CD4-CD8- stage of T cell development. We previously observed that thymocytes from RAG-2-/- mice exposed to gamma radiation differentiate from CD4-CD8- into CD4+CD8+ without TCR-beta chain rearrangement. We now report that irradiated RAG-2-/- thymocytes undergo direct somatic mutations at the p53 gene locus, and that p53 inactivation is associated with maturation of RAG2-/- thymocytes to the CD4+CD8+ stage. Generation of RAG2-/- and p53-/- double-deficient mice revealed that, in the absence of TCR-beta chain rearrangement, loss of p53 function is sufficient for CD4-CD8- thymocytes to differentiate into the CD4+CD8+ stage of T cell development. Our data provide evidence for a novel p53 mediated checkpoint in early thymocyte development that regulates the transition of CD4-CD8- into CD4+CD8+ thymocytes.

scholarly journals Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development.

1996 ◽  
Vol 93 (15) ◽  
pp. 7877-7881 ◽  
Author(s):  
G. Bouvier ◽  
F. Watrin ◽  
M. Naspetti ◽  
C. Verthuy ◽  
P. Naquet ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Gene Enhancer ◽  
T Cell Receptor Beta ◽  
Beta Gene ◽  
Receptor Beta

scholarly journals Gamma/delta lineage relationship within a consecutive series of human precursor T-cell neoplasms

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2508-2518 ◽  
Author(s):  
JP de Villartay ◽  
AB Pullman ◽  
R Andrade ◽  
E Tschachler ◽  
O Colamenici ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Consecutive Series ◽  
Gene Rearrangements ◽  
Gamma Delta ◽  
Delta Gene ◽  
Gene Usage ◽  
Rearrangement Process ◽  
Gamma Delta T Cell

Abstract We analyzed the gene rearrangements associated with the newly described delta T-cell receptor (TCR) gene from a series of 19 consecutive precursor T-cell (lymphoblastic) neoplasms that represent discrete stages surrounding the TCR gene rearrangement process. Significantly, the delta TCR gene showed rearrangement in most (13 of 19) of these T cells, and in addition it was rearranged in two cells displaying no rearrangement for any other TCR gene. Our survey showed three types of delta gene rearrangements associated with cell-surface TCR expression that presumably represent usage of three V delta genes. This analysis demonstrates (1) a major subclass of human precursor T-cell neoplasms belonging to the gamma/delta T-cell receptor-rearranging subtype; (2) a narrow repertoire of human V delta gene usage; and (3) the utility of delta gene rearrangements as a diagnostic clonal marker in precursor T lymphoblastic neoplasms.

T cell development and repertoire of mice expressing a single T cell receptor α chain

1995 ◽  
Vol 25 (9) ◽  
pp. 2650-2655 ◽  
Author(s):  
Daniel Brändle ◽  
Karin Brduscha-Riem ◽  
Adrian C. Hayday ◽  
Michael J. Owen ◽  
Hans Hengartner ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Α Chain
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