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 of T-cell receptor beta-chain genes during T-cell development.

1985 ◽  
Vol 82 (9) ◽  
pp. 2925-2929 ◽  
Author(s):  
W. Born ◽  
J. Yague ◽  
E. Palmer ◽  
J. Kappler ◽  
P. Marrack
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Beta Chain ◽  
T Cell Receptor Beta ◽  
Beta Chain Genes ◽  
Receptor Beta

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 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 Configuration and expression of the T cell receptor beta chain gene in human T-lymphotrophic virus I-infected cells.

1986 ◽  
Vol 163 (2) ◽  
pp. 383-399 ◽  
Author(s):  
R F Jarrett ◽  
H Mitsuya ◽  
D L Mann ◽  
J Cossman ◽  
S Broder ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Function ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Primary Tumor ◽  
Gene Rearrangement ◽  
Cell Receptor ◽  
Beta Chain ◽  
Beta Gene

We studied the configuration and expression of the gene encoding the beta chain of the T cell receptor (TCR beta) in cell lines and primary tumor cells infected by the human T cell leukemia/lymphoma (lymphotrophic) virus type I (HTLV-I). Most of the cell lines and all the primary tumor cells showed rearrangement of the TCR beta gene, and in each case the rearrangement was distinct. The majority of cases examined were clonal with respect to a particular TCR beta gene rearrangement. Primary tumor cells from one case (SD) were found to have a tandem duplication of a portion of chromosome 7; this appears to have resulted in the presence of three alleles of the TCR beta gene, each of which is arranged differently. This suggests that the chromosomal abnormality, and possibly infection by HTLV-I, occurred before TCR beta gene rearrangement. Cell lines infected by HTLV-I express levels of TCR beta mRNA similar to PHA stimulated lymphocytes, suggesting that this gene is not transcriptionally activated as a result of infection by HTLV-I. Cloned T cells of known antigen specificity that are infected by HTLV-I in vitro show impairment of immune function, including loss of antigen-specific responsiveness and the acquisition of alloreactivity. Comparison of the configuration of the TCR beta gene before and after infection revealed no changes detectable by Southern blot analysis. Levels of expression of the TCR beta gene at the mRNA level and surface expression of the T3 complex were also not significantly altered, suggesting that changes in immune function cannot be attributed to quantitative changes in the TCR molecule. The configuration of the TCR beta gene in primary tumor cells infected by HTLV-I was compared with that in the derived cell lines. In all pairs examined, the configuration in the primary tumor cells was different from that in the cell lines, strongly suggesting that the cells that grow in culture are not the original neoplastic cells.

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

Prognostic Significance of Molecular-Cytogenetic Abnormalities in Pediatric T-ALL Is Not Explained by Immunophenotypic Differences.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4220-4220
Author(s):  
Martine van Grotel ◽  
Anton W. Langerak ◽  
H. Berna Beverloo ◽  
Jessica G.C.A.M. Buijs-Gladdines ◽  
Nicole B. Burger ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Prognostic Significance ◽  
Cell Receptor ◽  
Cell Development ◽  
Cytogenetic Abnormalities ◽  
Molecular Cytogenetic ◽  
Poor Outcome ◽  
Notch1 Mutations

Abstract Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is characterized by recurrent chromosomal rearrangements that may have prognostic significance. T-ALL cases with specific aberrations may arrest at specific T-cell development stages. Two classification systems were developed to classify T-ALL into developmental subgroups, i.e. the European Group for the Immunological Characterization of Leukemias (EGIL) and the T-cell receptor (TCR) classification system. In this study, we investigated the relationship between molecular-cytogenetic abnormalities and T-cell development stage. We investigated whether arrest at specific T-cell stages explains the prognostic significance of molecular-cytogenetic abnormalities. To this aim, we extensively studied 72 pediatric T-ALL cases by FISH and RQ-PCR for the presence of genetic abnormalities and expression of transcription factors, by PCR and sequencing for NOTCH1 mutations and by flow-cytometry to determine the T-cell receptor status as well as CD marker expression. The median clinical follow-up was 5 years. HOX11 rearranged cases were CD1 positive consistent with a cortical stage, but as 4 out of 5 cases lacked cytoplasmatic-beta expression, developmental arrest may precede beta-selection. HOX11L2 was especially confined to immature and pre-AB developmental stages, but 3 out of 17 HOX11L2 mature cases were restricted to the γδ-lineage. TAL1 rearrangements were restricted to the αβ-lineage with most cases being TCRαβ positive. NOTCH1 mutations were present in all molecular-cytogenetic subgroups without restriction to a specific developmental stage. The CALM-AF10 translocation as detected in 3 T-ALL patients was significantly associated with early relapse. TAL1 or HOX11L2 rearrangements were associated with trends to good and poor outcome, respectively. Cases with high TAL1 expression levels also demonstrated a trend towards good outcome, whereas cases with the lowest TAL1 levels had a poor outcome and were mostly HOX11L2 or CALM-AF10 positive. NOTCH1 mutations did not predict for poor outcome. Classification into T-cell developmental subgroups did not predict for outcome. In conclusion, the present study shows that differences in outcome for various molecular-cytogenetic subgroups cannot be attributed to differences in T-cell maturation stage.

Sign in / Sign up

Export Citation Format

Share Document