scholarly journals Noncanonical Wnt signaling promotes apoptosis in thymocyte development

2007 ◽  
Vol 204 (13) ◽  
pp. 3077-3084 ◽  
Author(s):  
Huiling Liang ◽  
Andrew H. Coles ◽  
Zhiqing Zhu ◽  
Jennifer Zayas ◽  
Roland Jurecic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Wnt Signaling ◽  
T Cell Development ◽  
Cell Development ◽  
Thymocyte Development ◽  
Growth And Survival ◽  
Canonical Wnt

The Wnt–β-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt–Ca2+ signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of αβ lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4+CD8+ thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting β-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of β-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt–Ca2+ pathway alters canonical Wnt signaling and is critical for normal T cell development.

scholarly journals Spontaneous Intestinal Tumorigenesis inApc/Min+Mice Requires Altered T Cell Development with IL-17A

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wook-Jin Chae ◽  
Alfred L. M. Bothwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Mutation ◽  
Adoptive Transfer ◽  
Tumor Regression ◽  
T Cell Development ◽  
Cell Development ◽  
Intestinal Tumorigenesis

The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression. Here we address the inhibitory role of Tregs on intestinal tumorigenesis in theApc/Min+mouse model that resembles human familial adenomatous polyposis (FAP).Apc/Min+mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria. To address the role of heterozygousApcgene mutation in Tregs, we generatedFoxp3-Cre,Apcflox/+mice. Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer intoApc/Min+mice, demonstrating that the heterozygousApcgene mutation in Tregs does not induce the loss of control over tumor microenvironment. Adoptive transfer of in vitro generatedApc/Min+iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated fromApc/Min+mice thymus were impaired. We also showed that adoptively transferred IL-17A-deficientApc/Min+Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function ofApc/Min+Tregs. Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis inApc/Min+mice.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

scholarly journals Conditional Knockout Mice Reveal Distinct Functions for the Global Transcriptional Coactivators CBP and p300 in T-Cell Development

2006 ◽  
Vol 26 (3) ◽  
pp. 789-809 ◽  
Author(s):  
Lawryn H. Kasper ◽  
Tomofusa Fukuyama ◽  
Michelle A. Biesen ◽  
Fayçal Boussouar ◽  
Caili Tong ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Conditional Knockout ◽  
Specific Cell ◽  
Creb Binding Protein ◽  
Thymocyte Development ◽  
Transcriptional Coactivators

ABSTRACT The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300 flox ) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300 flox and a CBP conditional knockout allele (CBP flox ) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4− CD8− double-negative thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-positive thymocytes, but an increase in the percentage of CD8+ single-positive thymocytes seen in CBP mutant mice was not observed in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.

In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells

2007 ◽  
Vol 3 (1) ◽  
pp. 57-75 ◽  
Author(s):  
Ross La Motte-Mohs ◽  
Geneve Awong ◽  
Juan Carlos Zuniga-Pflucker
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
In Vitro Models ◽  
Human T Cell

scholarly journals New role for the (pro)renin receptor in T-cell development

Blood ◽  
2015 ◽  
Vol 126 (4) ◽  
pp. 504-507 ◽  
Author(s):  
Sabrina Geisberger ◽  
Ulrike Maschke ◽  
Matthias Gebhardt ◽  
Markus Kleinewietfeld ◽  
Arndt Manzel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Thymocyte Development ◽  
Key Points ◽  
Multiple Stages

Key Points PRR deletion in T cells drastically reduces the number of peripheral and thymic CD3+ T cells. We identify multiple stages of thymocyte development that require PRR expression.

scholarly journals Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM

Blood ◽  
2012 ◽  
Vol 120 (4) ◽  
pp. 789-799 ◽  
Author(s):  
Takeshi Isoda ◽  
Masatoshi Takagi ◽  
Jinhua Piao ◽  
Shun Nakagama ◽  
Masaki Sato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Chromosomal Translocation ◽  
Cell Development ◽  
Positive Phase ◽  
Deficient Mouse ◽  
Thymocyte Development ◽  
Immune Defect ◽  
Single Positive

Immune defect in ataxia telangiectasia patients has been attributed to either the failure of V(D)J recombination or class-switch recombination, and the chromosomal translocation in their lymphoma often involves the TCR gene. The ATM-deficient mouse exhibits fewer CD4 and CD8 single-positive T cells because of a failure to develop from the CD4+CD8+ double-positive phase to the single-positive phase. Although the occurrence of chromosome 14 translocations involving TCR-δ gene in ATM-deficient lymphomas suggests that these are early events in T-cell development, a thorough analysis focusing on early T-cell development has never been performed. Here we demonstrate that ATM-deficient mouse thymocytes are perturbed in passing through the β- or γδ-selection checkpoint, leading in part to the developmental failure of T cells. Detailed karyotype analysis using the in vitro thymocyte development system revealed that RAG-mediated TCR-α/δ locus breaks occur and are left unrepaired during the troublesome β- or γδ-selection checkpoints. By getting through these selection checkpoints, some of the clones with random or nonrandom chromosomal translocations involving TCR-α/δ locus are selected and accumulate. Thus, our study visualized the first step of multistep evolutions toward lymphomagenesis in ATM-deficient thymocytes associated with T-lymphopenia and immunodeficiency.

A Hypomorphic Cbfb Allele Reveals a Critical Dosage-Sensitive Function of Core Binding Factors at the Earliest Stages of T Cell Development.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 124-124
Author(s):  
Ivan Maillard ◽  
Laleh Talebian ◽  
Zhe Li ◽  
Yalin Guo ◽  
Daisuke Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Binding ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Hematopoietic Stem

Abstract The family of core binding factors includes the DNA-binding subunits Runx1-3 and the common non-DNA binding partner CBFβ. Runx1 and CBFβ are essential for the emergence of hematopoietic stem cells during fetal development, but not for stem cell maintenance during later ontogeny. Runx1 is also required for megakaryocyte differentiation, B cell development, and for the DN2 to DN3 transition in thymocyte development. Runx2/CBFβ are critical for normal osteogenesis, and Runx3 for CD4 silencing in CD8+ T cells, but their contribution to other steps of hematopoietic development is unknown. To examine the collective role of core binding factors in hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). CBFβ protein levels were reduced by approximately 2–3 fold in fetuses homozygous for the Cbfbrss allele (Cbfbrss/rss), and 3–4 fold in fetuses carrying one hypomorphic and one knockout allele (Cbfbrss/−). Cbfbrss/rss and Cbfbrss/− fetuses had normal erythroid and B cell development, and relatively mild abnormalities in megakaryocyte and granulocyte differentiation. In contrast, T cell development was very sensitive to an incremental reduction of CBFβ levels: mature thymocytes were decreased in Cbfbrss/rss fetuses, and virtually absent in Cbfbrss/−fetuses. We next assessed the development of Cbfbrss/rss and Cbfbrss/− fetal liver progenitors after transplantation to irradiated adult recipients, in competition with wild-type (wt) bone marrow cells. Wt, Cbfbrss/rss and Cbfbrss/− fetal progenitors replenished the erythroid, myeloid and B cell compartments equally well. The overall development of Cbfbrss/rss T cells was preserved, although CD4 expression was derepressed in double negative thymocytes. In Cbfbrss/− chimeras, mature thymocytes were entirely derived from competitor cells. Furthermore, the developmental block in Cbfbrss/− progenitors was present at the earliest stages of T cell development within the DN1 (ETP) and DN2 subsets. Our data define a critical CBFβ threshold for normal T cell development, and they situate an essential role of core binding factors during the earliest stages of T cell development. In addition, early thymopoiesis appeared more severely affected by reduced CBFβ dosage than by the lack of Runx1 (Ichikawa et al., Nat Med 2004; Growney et al., Blood 2005), suggesting that Runx2/3 may contribute to core binding factor activity in the T cell lineage.

scholarly journals Essential Role of Survivin, an Inhibitor of Apoptosis Protein, in T Cell Development, Maturation, and Homeostasis

2003 ◽  
Vol 199 (1) ◽  
pp. 69-80 ◽  
Author(s):  
Zheng Xing ◽  
Edward M. Conway ◽  
Chulho Kang ◽  
Astar Winoto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Developmental Stages ◽  
T Cell Development ◽  
Cell Development ◽  
Inhibitor Of Apoptosis ◽  
Proliferating Cells ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

Survivin is an inhibitor of apoptosis protein that also functions during mitosis. It is expressed in all common tumors and tissues with proliferating cells, including thymus. To examine its role in apoptosis and proliferation, we generated two T cell–specific survivin-deficient mouse lines with deletion occurring at different developmental stages. Analysis of early deleting survivin mice showed arrest at the pre–T cell receptor proliferating checkpoint. Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number. In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis. However, newborn thymocyte homeostatic and mitogen-induced proliferation of survivin-deficient T cells were greatly impaired. These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

Overlapping functions of human CD3δ and mouse CD3γ in αβ T-cell development revealed in a humanized CD3γ-deficient mouse

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3420-3427 ◽  
Author(s):  
Edgar Fernández-Malavé ◽  
Ninghai Wang ◽  
Manuel Pulgar ◽  
Wolfgang W. A. Schamel ◽  
Balbino Alarcón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Double Negative ◽  
Wild Type ◽  
Thymocyte Development ◽  
Double Positive ◽  
Deficient Mice ◽  
Αβ T Cells

Abstract Humans lacking the CD3γ subunit of the pre-TCR and TCR complexes exhibit a mild αβ T lymphopenia, but have normal T cells. By contrast, CD3γ-deficient mice are almost devoid of mature αβ T cells due to an early block of intrathymic development at the CD4–CD8– double-negative (DN) stage. This suggests that in humans but not in mice, the highly related CD3δ chain replaces CD3γ during αβ T-cell development. To determine whether human CD3δ (hCD3δ) functions in a similar manner in the mouse in the absence of CD3γ, we introduced an hCD3δ transgene in mice that were deficient for both CD3δ and CD3γ, in which thymocyte development is completely arrested at the DN stage. Expression of hCD3δ efficiently supported pre-TCR–mediated progression from the DN to the CD4+CD8+ double-positive (DP) stage. However, αβTCR-mediated positive and negative thymocyte selection was less efficient than in wild-type mice, which correlated with a marked attenuation of TCR-mediated signaling. Of note, murine CD3γ-deficient TCR complexes that had incorporated hCD3δ displayed abnormalities in structural stability resembling those of T cells from CD3γ-deficient humans. Taken together, these data demonstrate that CD3δ and CD3γ play a different role in humans and mice in pre-TCR and TCR function during αβ T-cell development.

scholarly journals Inflammatory Cytokines Regulate T-Cell Development from Blood Progenitor Cells in a Stage and Dose-Specifc Manner

2021 ◽  
Author(s):  
John M. Edgar ◽  
Peter W. Zandstra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
T Cell Maturation

ABSTRACTT-cell development from hematopoietic stem and progenitor cells (HSPCs) is tightly regulated through Notch pathway activation by the Notch ligands Delta-like (DL) 1 and 4 and Jagged-2. Other molecules, such as stem cell factor (SCF), FMS-like tyrosine kinase 3 ligand (Flt3L) and interleukin (IL)-7, play a supportive role in regulating the survival, differentiation, and proliferation of developing progenitor (pro)T-cells. Numerous other signaling molecules are known to instruct T-lineage development in vivo, but little work has been done to optimize their use for T-cell production in vitro. Using a defined T-lineage differentiation assay consisting of plates coated with the Notch ligand DL4 and adhesion molecule VCAM-1, we performed a cytokine screen that identified IL-3 and tumor necrosis factor α (TNFα) as enhancers of proT-cell differentiation and expansion. Mechanistically, we found that TNFα induced T-lineage differentiation through the positive regulation of T-lineage genes GATA3, TCF7, and BCL11b. TNFα also synergized with IL-3 to induce proliferation by upregulating the expression of the IL-3 receptor on CD34+ HSPCs, yielding 753.2 (532.4-1026.9; 5-95 percentile)-fold expansion of total cells after 14 days compared to 8.9 (4.3-21.5)-fold expansion in conditions without IL-3 and TNFα. We then optimized cytokine concentrations for T-cell maturation. Focusing on T-cell maturation, we used quantitative models to optimize dynamically changing cytokine requirements and used these to construct a three-stage assay for generating CD3+CD4+CD8+ and CD3+CD4−CD8+ T-cells. Our work provides new insight into T-cell development and a robust in vitro assay for generating T-cells to enable clinical therapies for treating cancer and immune disorders.

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