Pre-TCR signaling regulates IL-7 receptor α expression promoting thymocyte survival at the transition from the double-negative to double-positive stage

2003 ◽  
Vol 33 (7) ◽  
pp. 1968-1977 ◽  
Author(s):  
Cesar Trigueros ◽  
Katsuto Hozumi ◽  
Bruno Silva-Santos ◽  
Ludovica Bruno ◽  
Adrian C. Hayday ◽  
...  
Keyword(s):  
Double Negative ◽  
Tcr Signaling ◽  
Double Positive

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 c-Myc mediates pre-TCR-induced proliferation but not developmental progression

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2669-2677 ◽  
Author(s):  
Marei Dose ◽  
Irum Khan ◽  
Zhuyan Guo ◽  
Damian Kovalovsky ◽  
Andreas Krueger ◽  
...  
Keyword(s):  
Cell Receptor ◽  
Surface Expression ◽  
Double Negative ◽  
Tcr Signaling ◽  
Double Positive ◽  
Protein Levels ◽  
Developmental Progression ◽  
Severe Reduction

AbstractConstitutive and cell-autonomous signals emanating from the pre-T-cell receptor (pre-TCR) promote proliferation, survival and differentiation of immature thymocytes. We show here that induction of pre-TCR signaling resulted in rapid elevation of c-Myc protein levels. Cre-mediated thymocyte-specific ablation of c-Myc in CD25+CD44- thymocytes reduced proliferation and cell growth at the pre-TCR checkpoint, resulting in thymic hypocellularity and a severe reduction in CD4+CD8+ thymocytes. In contrast, c-Myc deficiency did not inhibit pre-TCR-mediated differentiation or survival. Myc-/- double-negative (DN) 3 cells progressed to the double-positive (DP) stage and up-regulated TCRαβ surface expression in the absence of cell proliferation, in vivo as well as in vitro. These observations indicate that distinct signals downstream of the pre-TCR are responsible for proliferation versus differentiation, and demonstrate that c-Myc is only required for pre-TCR-induced proliferation but is dispensable for developmental progression from the DN to the DP stage.

scholarly journals Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2217-2228 ◽  
Author(s):  
Susan V. Outram ◽  
Ariadne L. Hager-Theodorides ◽  
Divya K. Shah ◽  
Nicola J. Rowbotham ◽  
Ekati Drakopoulou ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Conditional Knockout ◽  
Indian Hedgehog ◽  
Double Negative ◽  
Wild Type ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive

Abstract We show that Indian Hedgehog (Ihh) regulates T-cell development and homeostasis in both fetal and adult thymus, controlling thymocyte number. Fetal Ihh−/− thymi had reduced differentiation to double-positive (DP) cell and reduced cell numbers compared with wild-type littermates. Surprisingly, fetal Ihh+/− thymi had increased thymocyte numbers and proportion of DP cells relative to wild type, indicating that Ihh also negatively regulates thymocyte development. In vitro treatment of thymus explants with exogenous recombinant Hedgehog protein promoted thymocyte development in Ihh−/− thymi but inhibited thymocyte development in Ihh+/−, confirming both positive and negative regulatory functions of Ihh. Analysis of Rag−/−Ihh+/− thymi showed that Ihh promotes T-cell development before pre–T-cell receptor (pre-TCR) signaling, but negatively regulates T-cell development only after pre-TCR signaling has taken place. We show that Ihh is most highly expressed by the DP population and that Ihh produced by DP cells feeds back to negatively regulate the differentiation and proliferation of their double-negative progenitors. Thus, differentiation from double-negative to DP cell, and hence the size of the DP population, is dependent on the concentration of Ihh in the thymus. Analysis of Ihh conditional knockout and heterozygote adult mice showed that Ihh also influences thymocyte number in the adult.

scholarly journals Critical and Multiple Roles for the CD3ε Intracytoplasmic Tail in Double Negative to Double Positive Thymocyte Differentiation

2009 ◽  
Vol 182 (8) ◽  
pp. 4844-4853 ◽  
Author(s):  
Jean-Francois Brodeur ◽  
Samantha Li ◽  
Maria da Silva Martins ◽  
Louise Larose ◽  
Vibhuti P. Dave
Keyword(s):  
Multiple Roles ◽  
Double Negative ◽  
Double Positive ◽  
Double Positive Thymocyte ◽  
Thymocyte Differentiation

scholarly journals Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination

2010 ◽  
Vol 207 (9) ◽  
pp. 1835-1841 ◽  
Author(s):  
Han-Yu Shih ◽  
Michael S. Krangel
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Three Dimensional ◽  
Double Negative ◽  
Thymocyte Development ◽  
Double Positive ◽  
Long Distance ◽  
Large Pool ◽  
Antigen Receptor Loci

Studies have suggested that antigen receptor loci adopt contracted conformations to promote long-distance interactions between gene segments during V(D)J recombination. The Tcra/Tcrd locus is unique because it undergoes highly divergent Tcrd and Tcra recombination programs in CD4−CD8− double negative (DN) and CD4+CD8+ double positive (DP) thymocytes, respectively. Using three-dimensional fluorescence in situ hybridization, we asked whether these divergent recombination programs are supported by distinct conformational states of the Tcra/Tcrd locus. We found that the 3′ portion of the locus is contracted in DN and DP thymocytes but not in B cells. Remarkably, the 5′ portion of the locus is contracted in DN thymocytes but is decontracted in DP thymocytes. We propose that the fully contracted conformation in DN thymocytes allows Tcrd rearrangements involving Vδ gene segments distributed over 1 Mb, whereas the unique 3′-contracted, 5′-decontracted conformation in DP thymocytes biases initial Tcra rearrangements to the most 3′ of the available Vα gene segments. This would maintain a large pool of distal 5′ Vα gene segments for subsequent rounds of recombination. Thus, distinct contracted conformations of the Tcra/Tcrd locus may facilitate a transition from a Tcrd to a Tcra mode of recombination during thymocyte development.

scholarly journals β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5463-5472 ◽  
Author(s):  
Zhuyan Guo ◽  
Marei Dose ◽  
Damian Kovalovsky ◽  
Rui Chang ◽  
Jennifer O'Neil ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymphoblastic Leukemia ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Notch Receptors ◽  
Single Positive ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Genetic Events ◽  
Notch Activation

AbstractActivation of β-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated β-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. β-Catenin–induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized β-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in β-catenin–induced lymphomas. Thus, β-catenin activation may provide a mechanism for the induction of T-cell–acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

scholarly journals Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation

2004 ◽  
Vol 199 (12) ◽  
pp. 1719-1724 ◽  
Author(s):  
Batu Erman ◽  
Terry I. Guinter ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Double Negative ◽  
Antigen Receptors ◽  
Double Positive ◽  
Recombination Activating Gene ◽  
Thymocyte Differentiation ◽  
Deficient Mice

During T cell development in the thymus, pre–T cell receptor (TCR) complexes signal CD4− CD8− (double negative [DN]) thymocytes to differentiate into CD4+ CD8+ (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as αβ TCR or αγ TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although αγ TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if αβ TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined αβ TCR transgenes in recombination activating gene 2−/− pre-Tα−/− double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the αβ TCR transgenes. In this way, this study definitively demonstrates that αβ TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic αβ TCRs signal the DN to DP transition even in the absence of their specific MHC–peptide ligands.

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