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Cited by 102T-cell and B-cell ImmunologyDevelopmental Biology and Gene RegulationHematopoietic Stem Cell Transplantation

An early decrease in Notch activation is required for human TCR-αβ lineage differentiation at the expense of TCR-γδ T cells

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Van de Walle, Inge, De Smet, Greet, De Smedt, Magda, Vandekerckhove, Bart, Leclercq, Georges, Plum, Jean, Taghon, Tom·2009·Blood
DOI 10.1182/blood-2008-06-164871
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Abstract

Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor αβ (TCR-αβ) versus TCR-γδ lineage decision is still unclear. Although it is clear in the mouse that TCR-γδ development is less Notch dependent compared with TCR-αβ differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and γδ T cells but inhibits differentiation toward the αβ lineage. Reducing the amount of Notch activation rescues αβ-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during αβ-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-γδ development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.

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  • Numerous signals impact γδ T cell lineage including TCR signal strength, notch signaling, IL-7R signaling, and the presence of DP thymocytes.

    “Numerous signals impact on the γδ T cell lineage including, TCR signal strength, notch signaling, IL-7R signaling and the presence of DP thymocytes [6]–[10].”

    From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [8]

    The Introduction and Discussion say that TCR signal strength and Notch signaling influence the αβ/γδ lineage decision. The section “IL-7 cannot compensate Notch-dependent γδ T-cell development” shows that changing IL-7 levels affects γδ T-cell numbers, although it does not directly test IL-7R signaling. The paper reports DP thymocytes as an outcome of altered Notch signaling, but does not show that their presence itself affects the γδ lineage. Page numbers were not provided for these passages. (LLM, conf=0.85)

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Cited by

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Authors
Van de Walle, I., De Smet, G., De Smedt, M., Vandekerckhove, B., Leclercq, G., Plum, J., & Taghon, T.
Affiliations
  • Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium
  • Ghent University Hospital (BE)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2009-03-26
Volume
113
Issue
13
Pages
2988-2998
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2008-06-164871
OpenAlex
W2014422435
Cited by
102
References
1
Citations by year
2026: 1 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 1 · 2014: 7 · 2013: 8 · 2012: 9
FWCI
3.19
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Funders
Amgen
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
Notch signaling, T cell development, lineage commitment, DTX1, RUNX3, IL-7, Notch target genes
MeSH terms
Cell Differentiation, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Stem Cells, T-Lymphocytes, Gene Rearrangement, T-Lymphocyte, Signal Transduction, Down-Regulation, Interleukin-7, Receptors, Antigen, T-Cell, gamma-delta, Receptors, Antigen, T-Cell, alpha-beta, Cell Lineage, Gene Expression Profiling, Receptors, Notch

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