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Cited by 351T-cell and B-cell ImmunologyDevelopmental Biology and Gene RegulationGenomics and Chromatin Dynamics

Reprogramming of Committed T Cell Progenitors to Macrophages and Dendritic Cells by C/EBPα and PU.1 Transcription Factors

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Laiosa, Catherine V., Stadtfeld, Matthias, Xie, Huafeng, de Andres-Aguayo, Luisa, Graf, Thomas·2006·Immunity
DOI 10.1016/j.immuni.2006.09.011
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Abstract

The differentiation potential of T lineage cells becomes restricted soon after entry of multipotent precursors into the thymus and is accompanied by a downregulation of the transcription factors C/EBP alpha and PU.1. To investigate this restriction point, we have expressed C/EBP alpha and PU.1 in fully committed pre-T cells and found that C/EBP alpha (and C/EBP beta) induced the formation of functional macrophages. In contrast, PU.1 converted them into myeloid dendritic cells under identical culture conditions. C/EBP alpha-induced reprogramming is complex because upregulation of some but not all myelomonocytic markers required endogenous PU.1. Notch signaling partially inhibited C/EBP alpha-induced macrophage formation and completely blocked PU.1-induced dendritic cell formation. Likewise, expression of intracellular Notch or the transcription factor GATA-3 inhibited C/EBP alpha-induced lineage conversion. Our data show that committed T cell progenitors remain susceptible to the lineage instructive effects of myeloid transcription factors and suggest that Notch signaling induces T lineage restriction by downregulating C/EBP alpha and PU.1 in multilineage precursors.

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  • Added PU.1 can enhance pro-T cell proliferation in response to cytokine cocktails containing high levels of SCF and Flt3 ligand or myeloid growth factors.

    “added PU.1 can enhance pro-T cell proliferation in response to cytokine cocktails containing high levels of Stem Cell Factor (Kit ligand) and Flt3 ligand or myeloid growth factors (38, 50)”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [50]

    The Results (page unavailable) report that PU.1-expressing T-lineage cells increased in number when cultured with myeloid cytokines, and that PU.1 increased cell numbers in another culture condition. They do not establish enhanced pro-T-cell proliferation specifically in response to high levels of SCF and Flt3 ligand; the reported increase in cell number is not itself a proliferation measurement. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Re-expression of PU.1 after T-cell commitment turns on myeloid genes and can transform later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells.

    “re-expression of PU.1 after T-cell commitment turns on myeloid genes and readily transforms later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells (46–50).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [50]

    The Discussion (page not available) says enforced PU.1 expression in committed pre-T cells induced cells resembling myeloid dendritic cells, and that PU.1 induces dendritic genes and a subset of myeloid genes. It distinguishes this from macrophage formation, which it attributes to C/EBPα and C/EBPβ; the cited passages do not report PU.1 producing promyelocytic-like cells. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • PU.1 actions are Notch-sensitive.

    “PU.1 actions are Notch-sensitive.”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [50]

    The Discussion reports that activated Notch completely inhibits PU.1-driven Mac-1 upregulation, supporting Notch sensitivity for that action. It also says Notch does not impair PU.1's ability to block T-cell differentiation, so the unqualified statement is broader than the finding. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Instead of re-acquiring a progenitor-like state, cells appear to trans-differentiate to a dendritic-cell or macrophage developmental program.

    “Instead of re-acquiring aspects of a progenitor-like state, the cells appear to trans-differentiate to a dendritic-cell or macrophage developmental program (48, 50, 58).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [50]

    The Discussion reports that committed pre-T cells transdifferentiated into macrophages after C/EBP expression, while PU.1 produced cells resembling myeloid dendritic cells. It rules out outgrowth of inadvertent myeloid progenitors, but does not establish that the reprogrammed cells never transiently re-acquired aspects of a progenitor-like state. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Even artificially high-level PU.1 can redirect differentiation to myeloid or dendritic fates only if Notch signaling is reduced.

    “Even artificially high-level PU.1 could only redirect the differentiation of the cells to myeloid or dendritic fates if Notch signaling were reduced (49, 50, 58).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [50]

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References 61 · Cited by 351

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Authors
Laiosa, C. V., Stadtfeld, M., Xie, H., de Andres-Aguayo, L., & Graf, T.
Affiliations
Albert Einstein College of Medicine (US)
Corresponding author
Graf, Thomas
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2006-11
Volume
25
Issue
5
Pages
731-744
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2006.09.011
OpenAlex
W1971463847
Cited by
351
References
61
Citations by year
2026: 10 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 12 · 2019: 23 · 2018: 15 · 2017: 15 · 2016: 16 · 2015: 22 · 2014: 18 · 2013: 32 · 2012: 25
FWCI
8.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01 CA89590-01, R01CA089590)
  • National Institute of General Medical Sciences (T32GM007288)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
T cell progenitors, macrophage differentiation, dendritic cell differentiation, C/EBPα, PU.1, lineage conversion, Notch signaling, GATA3, C/EBPβ, pre-T cells
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Dendritic Cells, Flow Cytometry, Gene Expression Regulation, Macrophages, Proto-Oncogene Proteins, Stem Cells, T-Lymphocytes, Trans-Activators, Gene Expression, Cell Lineage, Reverse Transcriptase Polymerase Chain Reaction, CCAAT-Enhancer-Binding Protein-alpha, Mice

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