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Cited by 152T-cell and B-cell ImmunologyDevelopmental Biology and Gene RegulationHematopoietic Stem Cell Transplantation

Fine-Scale Staging of T Cell Lineage Commitment in Adult Mouse Thymus

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Yui, Mary A, Feng, Ni, Rothenberg, Ellen V·2010·The Journal of Immunology
DOI 10.4049/jimmunol.1000679PMC PMC4091773
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Abstract

T cell development is marked by the loss of alternative lineage choices accompanying specification and commitment to the T cell lineage. Commitment occurs between the CD4 and CD8 double-negative (DN) 2 and DN3 stages in mouse early T cells. To determine the gene regulatory changes that accompany commitment, we sought to distinguish and characterize the earliest committed wild-type DN adult thymocytes. A transitional cell population, defined by the first downregulation of surface c-Kit expression, was found to have lost the ability to differentiate into dendritic cells and NK cells when cultured without Notch-Delta signals. In the presence of Notch signaling, this subset generates T lineage descendants in an ordered precursor–product relationship between DN2, with the highest levels of surface c-Kit, and c-Kit–low DN3 cells. These earliest committed cells show only a few differences in regulatory gene expression, compared with uncommitted DN2 cells. They have not yet established the full expression of Notch-related and T cell differentiation genes characteristic of DN3 cells before β selection. Instead, the downregulation of select stem cell and non-T lineage genes appears to be key to the extinction of alternative lineage choices.

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  • In mouse, natural loss of access to dendritic cell and granulocyte programs agrees with the timing of PU.1 downregulation.

    “there is good agreement between the cells' natural loss of access to the dendritic cell and granulocyte programs, on the one hand, and the timing of PU.1 downregulation, on the other hand (33, 39–42).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [33]

    The Results sections on DC and NK developmental potential and on non-T-cell genes (page unavailable) place loss of dendritic-cell potential and PU.1 downregulation at the DN2a-to-DN2b transition. The paper assays dendritic-cell and NK-cell potential, but does not establish the timing of lost granulocyte potential. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ETP and DN2 cells can generate myeloid cells if removed from the thymus, whereas pro-T cells past PU.1 expression (DN3 or later) do not make myeloid cells under these conditions.

    “Whereas ETP and DN2 cells can generate myeloid cells if removed from the thymus, pro-T cells that have differentiated past the stage of PU.1 expression in the thymus (i.e., from the DN2 stage to the DN3 stage or later) do not make myeloid cells under these conditions”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [33]

    The Introduction says DN2 cells retain possible myeloid potential while DN3 cells are committed to the T lineage. The Results section on DC and NK potential reports that ETP and DN2a cells produce alternative lineages without Notch signaling, whereas DN2b and DN3a cells produce few, if any, DCs or NK cells. It does not directly test myeloid production at those stages, and the gene-expression Results place the first decline in PU.1 at DN2b, before DN3. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Some PU.1 expression is still detectable at later stages, in the same individual cells that go through T-cell commitment marked by Bcl11b activation.

    “intracellular protein staining confirmed that some PU.1 expression is still detectable at later stages, in the same individual cells that go through T-cell commitment (marked by activation of the Bcl11b gene) (33, 93).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [33]

    The Results section ('Major changes in Notch-related genes follow declines in non-T cell genes at commitment'; page unavailable) reports intracellular staining showing reduced but detectable PU.1 protein in individual newly committed DN2b cells. The Results section ('T lineage identity genes'; page unavailable) places the major Bcl11b upregulation before commitment, but does not show Bcl11b activation and PU.1 expression measured in the same individual cells. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These stages span multiple cell cycles in vivo and in vitro.

    “These stages span multiple cell cycles in vivo and in vitro (33, 39, 67, 124).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [33]

    The Results section, “DN2b cells are distinct from DN3 cells” (page unavailable), reports that cultured DN2b cells retained CD25 after 5–8 cell divisions, supporting the in vitro portion. Our copy does not establish that these stages span multiple cell cycles in vivo. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Precursors that give rise to committed T cells express PU.1 at RNA and protein levels for multiple cell divisions after thymic differentiation begins.

    “the precursors that give rise to committed T cells express PU.1 at both RNA and protein levels for multiple cell divisions after these cells begin to differentiate in the thymus (32, 33).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [33]

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Research works printed but not linked: 49

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Authors
Yui, M. A., Feng, N., & Rothenberg, E. V.
Affiliations
California Institute of Technology (US)
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2010-07-01
Volume
185
Issue
1
Pages
284-293
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1000679
PMC
PMC4091773
OpenAlex
W2118524018
Cited by
152
References
56
Citations by year
2026: 3 · 2025: 4 · 2024: 7 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 11 · 2018: 8 · 2017: 5 · 2016: 8 · 2015: 8 · 2014: 8 · 2013: 14 · 2012: 9
FWCI
5.36
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
  • California Institute of Technology
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R01AI064590)
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
T cell lineage commitment, T cell development, double-negative thymocytes, Notch signaling, dendritic cell differentiation, NK cell differentiation
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Female, Gene Expression Regulation, Mice, Inbred C57BL, Mice, Transgenic, Stem Cells, Thymus Gland, Down-Regulation, Up-Regulation, T-Lymphocyte Subsets, Mice, Inbred NOD, Cellular Senescence, Coculture Techniques, Cell Lineage, Cell Proliferation, Mice, Receptor, Notch1

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