scholarly journals Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor–Ligand Interactions

2004 ◽  
Vol 200 (4) ◽  
pp. 469-479 ◽  
Author(s):  
Thomas M. Schmitt ◽  
Maria Ciofani ◽  
Howard T. Petrie ◽  
Juan Carlos Zúñiga-Pflücker
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Stromal Cells ◽  
Cell Lineage ◽  
Notch Receptor ◽  
Lineage Specification ◽  
Cell Specification ◽  
Receptor Ligand ◽  
Ligand Interactions

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25− (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor–ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.

scholarly journals HEB in the Spotlight: Transcriptional Regulation of T-Cell Specification, Commitment, and Developmental Plasticity

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Marsela Braunstein ◽  
Michele K. Anderson
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Gene Network ◽  
Developmental Plasticity ◽  
Nk Cell ◽  
Cell Lineage ◽  
E Proteins ◽  
Cell Specification ◽  
Synergistic Interactions ◽  
Multipotent Progenitors

The development of T cells from multipotent progenitors in the thymus occurs by cascades of interactions between signaling molecules and transcription factors, resulting in the loss of alternative lineage potential and the acquisition of the T-cell functional identity. These processes require Notch signaling and the activity of GATA3, TCF1, Bcl11b, and the E-proteins HEB and E2A. We have shown that HEB factors are required to inhibit the thymic NK cell fate and that HEBAlt allows the passage of T-cell precursors from the DN to DP stage but is insufficient for suppression of the NK cell lineage choice. HEB factors are also required to enforce the death of cells that have not rearranged their TCR genes. The synergistic interactions between Notch1, HEBAlt, HEBCan, GATA3, and TCF1 are presented in a gene network model, and the influence of thymic stromal architecture on lineage choice in the thymus is discussed.

scholarly journals Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

2012 ◽  
Vol 209 (4) ◽  
pp. 713-728 ◽  
Author(s):  
Keunwook Lee ◽  
Ki Taek Nam ◽  
Sung Hoon Cho ◽  
Prathyusha Gudapati ◽  
Yoonha Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Lymphoblastic Leukemia ◽  
Notch Receptor ◽  
Leukemic Cells ◽  
Cell Fate Decisions ◽  
Proliferation And Differentiation ◽  
Physiological Outcomes

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.

scholarly journals Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

2017 ◽  
Vol 114 (23) ◽  
pp. 5800-5807 ◽  
Author(s):  
William J. R. Longabaugh ◽  
Weihua Zeng ◽  
Jingli A. Zhang ◽  
Hiroyuki Hosokawa ◽  
Camden S. Jansen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Notch Signaling ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
T Cell Development ◽  
Cell Specification ◽  
Gene Regulatory

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.

scholarly journals Notch Signaling in T-Cell Development and T-ALL

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaoyu Li ◽  
Harald von Boehmer
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Notch Signaling Pathway ◽  
Lineage Specification ◽  
Evolutionarily Conserved ◽  
Multiple Levels ◽  
Multicellular Organisms ◽  
T Cell Maturation

The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and αβ versus γδ lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.

scholarly journals Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength

2013 ◽  
Vol 210 (4) ◽  
pp. 683-697 ◽  
Author(s):  
Inge Van de Walle ◽  
Els Waegemans ◽  
Jelle De Medts ◽  
Greet De Smet ◽  
Magda De Smedt ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Notch Receptor ◽  
Γδ T Cell ◽  
Receptor Ligand ◽  
Lineage Differentiation ◽  
Notch Signal ◽  
Ligand Interactions ◽  
Notch Activation

In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor–ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ development. Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor–ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.

scholarly journals Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation

2001 ◽  
Vol 194 (7) ◽  
pp. 991-1002 ◽  
Author(s):  
Ana C. Jaleco ◽  
Hélia Neves ◽  
Erik Hooijberg ◽  
Paula Gameiro ◽  
Nuno Clode ◽  
...  
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
De Novo ◽  
Cell Lineage ◽  
Differential Effects ◽  
Cell Lineages ◽  
A Cell ◽  
Fate Decision ◽  
Notch Ligands

Notch signaling is known to differentially affect the development of lymphoid B and T cell lineages, but it remains unclear whether such effects are specifically dependent on distinct Notch ligands. Using a cell coculture assay we observed that the Notch ligand Delta-1 completely inhibits the differentiation of human hematopoietic progenitors into the B cell lineage while promoting the emergence of cells with a phenotype of T cell/natural killer (NK) precursors. In contrast, Jagged-1 did not disturb either B or T cell/NK development. Furthermore, cells cultured in the presence of either Delta-1 or Jagged-1 can acquire a phenotype of NK cells, and Delta-1, but not Jagged-1, permits the emergence of a de novo cell population coexpressing CD4 and CD8. Our results thus indicate that distinct Notch ligands can mediate differential effects of Notch signaling and provide a useful system to further address cell-fate decision processes in lymphopoiesis.

scholarly journals Core binding factors are necessary for natural killer cell development and cooperate with Notch signaling during T-cell specification

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 480-492 ◽  
Author(s):  
Yalin Guo ◽  
Ivan Maillard ◽  
Sankhamala Chakraborti ◽  
Ellen V. Rothenberg ◽  
Nancy A. Speck
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Lineage Specification ◽  
Cell Specification ◽  
Developmental Program ◽  
Binding Subunit

Abstract CBFβ is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBFβ levels display profound, early defects in T-cell but not B-cell development. Here we show that CBFβ is also required at very early stages of natural killer (NK)–cell development. We also demonstrate that T-cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T-cell expansion or differentiation of CBFβ insufficient cells, nor can overexpression of Runx1 or CBFβ overcome a lack of Notch signaling. Therefore, the ability of the prethymic cell to respond appropriately to Notch is dependent on CBFβ, and both signals converge to activate the T-cell developmental program.

scholarly journals E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment

2006 ◽  
Vol 203 (5) ◽  
pp. 1329-1342 ◽  
Author(s):  
Tomokatsu Ikawa ◽  
Hiroshi Kawamoto ◽  
Ananda W. Goldrath ◽  
Cornelis Murre
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
E Proteins ◽  
Lineage Specification ◽  
Helix Loop Helix ◽  
Hes1 Expression ◽  
Cell Commitment

The helix-loop-helix protein, E47, is essential for both B- and T-lineage development. Here we demonstrate that in vitro E47 and Notch signaling act in concert to promote T cell development from fetal hematopoieitic progenitors and to restrain development into the natural killer and myeloid cell lineages. The expression of an ensemble of genes associated with Notch signaling is activated by E47, and additionally, Notch signaling and E47 act in parallel pathways to induce a T lineage–specific program of gene expression. Enforced expression of the intracellular domain of Notch rescues the developmental arrest at the T cell commitment stage in E2A-deficient fetal thymocytes. Finally, we demonstrate that regulation of Hes1 expression by Notch signaling and E47 is strikingly similar to that observed during Drosophila melanogaster sensory development. Based on these observations, we propose that in developing fetal thymocytes E47 acts to induce the expression of an ensemble of genes involved in Notch signaling, and that subsequently E47 acts in parallel with Notch signaling to promote T-lineage maturation.

scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

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