The T Cell Receptor: Its Repertoire and Role in Thymocyte Development

1987 ◽  
pp. 1-12 ◽  
Author(s):  
Philippa Marrack ◽  
Marcia McDuffie ◽  
Willi Born ◽  
Marica Blackman ◽  
Charles Hannum ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Thymocyte Development

scholarly journals The transcription factor Gli3 regulates differentiation of fetal CD4–CD8– double-negative thymocytes

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1296-1304 ◽  
Author(s):  
Ariadne L. Hager-Theodorides ◽  
Johannes T. Dessens ◽  
Susan V. Outram ◽  
Tessa Crompton
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Double Negative ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Dose Dependent

AbstractGlioblastoma 3 (Gli3) is a transcription factor involved in patterning and oncogenesis. Here, we demonstrate a role for Gli3 in thymocyte development. Gli3 is differentially expressed in fetal CD4–CD8– double-negative (DN) thymocytes and is most highly expressed at the CD44+ CD25– DN (DN1) and CD44–CD25– (DN4) stages of development but was not detected in adult thymocytes. Analysis of null mutants showed that Gli3 is involved at the transitions from DN1 to CD44+ CD25+ DN (DN2) cell and from DN to CD4+CD8+ double-positive (DP) cell. Gli3 is required for differentiation from DN to DP thymocyte, after pre–T-cell receptor (TCR) signaling but is not necessary for pre-TCR–induced proliferation or survival. The effect of Gli3 was dose dependent, suggesting its direct involvement in the transcriptional regulation of genes controlling T-cell differentiation during fetal development.

scholarly journals Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

1993 ◽  
Vol 178 (6) ◽  
pp. 1867-1875 ◽  
Author(s):  
C N Levelt ◽  
R Carsetti ◽  
K Eichmann
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
T Cell Receptor ◽  
Alternative Hypothesis ◽  
Cell Receptor ◽  
Surface Expression ◽  
Beta Chain ◽  
Thymocyte Development ◽  
Double Positive ◽  
Highly Correlated

Recent studies have shown that maturation of CD4-8- double negative (DN) thymocytes to the CD4+8+ double positive (DP) stage is dependent on expression of the T cell receptor (TCR)-beta polypeptide. The exact mechanism by which the TCR-beta chain regulates this maturation step remains unknown. Previous experiments had suggested that in the presence of some TCR+ thymocytes, additional DN thymocytes not expressing a TCR-beta chain may be recruited to mature to the DP stage. The recent demonstration of an immature TCR-beta-CD3 complex on early thymocytes lead to the alternative hypothesis that signal transduction through an immature TCR-CD3 complex may induce maturation to the DP stage. In the latter case, maturation to the DP stage would depend on the expression of TCR-beta-CD3 in the same cell. We examined these two hypotheses by studying the expression of the intra- and extracellular CD3 epsilon, CD3 zeta, and TCR-beta polypeptides in intrathymic subpopulations during embryogenesis. CD3 epsilon and CD3 zeta were expressed intracellularly 2 and 1 d, respectively, before intracellular expression of the TCR-beta chain, potentially allowing immediate surface expression of an immature TCR-beta-CD3 complex as soon as functional rearrangement of a TCR-beta gene locus has been accomplished. Calcium mobilization could be induced by stimulation with anti-CD3 epsilon mAb as soon as intracellular TCR-beta was detectable, suggesting that a functional TCR-beta-CD3 complex is indeed expressed on the surface of early thymocytes. From day 17 on, most cells were in the DP stage, and over 95% of the DP cells expressed on the TCR-beta chain intracellularly. At day 19 of gestation, extremely low concentrations of TCR-beta chain and CD3 epsilon were detectable on the cell surface of nearly all thymocytes previously thought to be TCR-CD3 negative. These findings strongly support the hypothesis that maturation to the DP stage depends on surface expression of and subsequent signal transduction through an immature TCR-beta-CD3 complex and suggest that maturation to the DP stage by recruitment, if it occurs at all, is of minor relevance.

RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development

2006 ◽  
Vol 7 (11) ◽  
pp. 1182-1190 ◽  
Author(s):  
Yi Gu ◽  
Hee-Don Chae ◽  
Jamie E Siefring ◽  
Aparna C Jasti ◽  
David A Hildeman ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
Thymocyte Development ◽  
T Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals Regulation of pre-T cell receptor (pT alpha-TCR beta) gene expression during human thymic development.

1996 ◽  
Vol 184 (2) ◽  
pp. 519-530 ◽  
Author(s):  
A R Ramiro ◽  
C Trigueros ◽  
C Márquez ◽  
J L San Millán ◽  
M L Toribio
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Beta Chain ◽  
Thymocyte Development ◽  
Gene Encoding ◽  
Thymic Development ◽  
Alpha Beta ◽  
Beta Gene

In murine T cell development, early thymocytes that productively rearrange the T cell receptor (TCR) beta locus are selected to continue maturation, before TCR alpha expression, by means of a pre-TCR alpha- (pT alpha-) TCR beta heterodimer (pre-TCR). The aim of this study was to identify equivalent stages in human thymocyte development. We show here that variable-diversity-joining region TCR beta rearrangement and the expression of full-length TCR beta transcripts have been initiated in some immature thymocytes at the TCR alpha/beta- CD4+CD8- stage, and become common in a downstream subset of TCR alpha/beta- CD4+CD8+ thymocytes that is highly enriched in large cycling cells. TCR beta chain expression was hardly detected in TCR alpha/beta- CD4+CD8- thymocytes, whereas cytoplasmic TCR beta chain was found in virtually all TCR alpha/beta- CD4+CD8+ blasts. In addition, a TCR beta complex distinct from the mature TCR alpha/beta heterodimer was immunoprecipitated only from the latter subset. cDNA derived from TCR alpha/beta- CD4+CD8+ blasts allowed us to identify and clone the gene encoding the human pT alpha chain, and to examine its expression at different stages of thymocyte development. Our results show that high pT alpha transcription occurs only in CD4+CD8- and CD4+CD8+ TCR alpha/beta- thymocytes, whereas it is weaker in earlier and later stages of development. Based on these results, we propose that the transition from TCR alpha/beta- CD4+CD8- to TCR alpha/beta- CD4+CD8+ thymocytes represents a critical developmental stage at which the successful expression of TCR beta promotes the clonal expansion and further maturation of human thymocytes, independent of TCR alpha.

scholarly journals Restricting Zap70 Expression to CD4+CD8+ Thymocytes Reveals a T Cell Receptor–dependent Proofreading Mechanism Controlling the Completion of Positive Selection

2003 ◽  
Vol 197 (3) ◽  
pp. 363-373 ◽  
Author(s):  
Xiaolong Liu ◽  
Anthony Adams ◽  
Kathryn F. Wildt ◽  
Bruce Aronow ◽  
Lionel Feigenbaum ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Novel Approach ◽  
Single Positive ◽  
Tcr Signals

Although T cell receptor (TCR) signals are essential for intrathymic T cell–positive selection, it remains controversial whether they only serve to initiate this process, or whether they are required throughout to promote thymocyte differentiation and survival. To address this issue, we have devised a novel approach to interfere with thymocyte TCR signaling in a developmental stage-specific manner in vivo. We have reconstituted mice deficient for Zap70, a tyrosine kinase required for TCR signaling and normally expressed throughout T cell development, with a Zap70 transgene driven by the adenosine deaminase (ADA) gene enhancer, which is active in CD4+CD8+ thymocytes but inactive in CD4+ or CD8+ single-positive (SP) thymocytes. In such mice, termination of Zap70 expression impaired TCR signal transduction and arrested thymocyte development after the initiation, but before the completion, of positive selection. Arrested thymocytes had terminated Rag gene expression and up-regulated TCR and Bcl-2 expression, but failed to differentiate into mature CD4 or CD8 SP thymocytes, to be rescued from death by neglect or to sustain interleukin 7Rα expression. These observations identify a TCR-dependent proofreading mechanism that verifies thymocyte TCR specificity and differentiation choices before the completion of positive selection.

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.

scholarly journals Requirement for p56lck tyrosine kinase activation in T cell receptor-mediated thymic selection.

1996 ◽  
Vol 184 (3) ◽  
pp. 931-943 ◽  
Author(s):  
K Hashimoto ◽  
S J Sohn ◽  
S D Levin ◽  
T Tada ◽  
R M Perlmutter ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Selection Process ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Thymocyte Development ◽  
Alpha Beta ◽  
Lck Protein

The nonreceptor protein tyrosine kinase p56lck (Lck) serves as a fundamental regulator of thymocyte development by delivering signals from the pre-T cell receptor (pre-TCR) that permit subsequent maturation. However, considerable evidence supports the view that Lck also participates in signal transduction from the mature TCR. We have tested this conjecture by expressing a dominant-negative form of Lck under the control of a promoter element (the distal lck promoter) that directs high expression in CD4+CD8+ thymocytes, mature thymocytes, and peripheral T cells, thereby avoiding, complications that result from the well-documented ability of dominant-negative Lck to block very early events in thymocyte maturation. Here we report that expression of the catalytically inactive Lck protein at twice normal concentrations inhibits thymocyte positive selection by as much as 80%, while leaving other aspects of cell maturation intact. This effect was studied in more detail in mice simultaneously bearing the male-specific H-Y alpha/beta TCR transgene and ovalbumin-specific DO10 alpha/beta TCR transgene, where even equimolar expression of the dominant-negative Lck protein substantially vitiated the positive selection process. Although deletion of H-Y alpha/beta thymocytes proceeded normally in male mice despite the presence of catalytically inactive Lck, modest inhibition of superantigen-mediated deletion was in some cases observed. These data further implicate Lck in the propagation of all TCR-derived signals, and indicate that even very modest deficiencies in the representation of functional Lck molecules could in humans, profoundly alter the character of the peripheral TCR repertoire.

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