Enforced Expression of Spi-B Reverses T Lineage Commitment and Blocks β-Selection
Open accessAbstract
The molecular changes that restrict multipotent murine thymocytes to the T cell lineage and render them responsive to Ag receptor signals remain poorly understood. In this study, we report our analysis of the role of the Ets transcription factor, Spi-B, in this process. Spi-B expression is acutely induced coincident with T cell lineage commitment at the CD4−CD8−CD44−CD25+ (DN3) stage of thymocyte development and is then down-regulated as thymocytes respond to pre-TCR signals and develop beyond the β-selection checkpoint to the CD4−CD8−CD44−CD25− (DN4) stage. We found that dysregulation of Spi-B expression in DN3 thymocytes resulted in a dose-dependent perturbation of thymocyte development. Indeed, DN3 thymocytes expressing approximately five times the endogenous level of Spi-B were arrested at the β-selection checkpoint, due to impaired induction of Egr proteins, which are important molecular effectors of the β-selection checkpoint. T lineage-committed DN3 thymocytes expressing even higher levels of Spi-B were diverted to the dendritic cell lineage. Thus, we demonstrate that the prescribed modulation of Spi-B expression is important for T lineage commitment and differentiation beyond the β-selection checkpoint; and we provide insight into the mechanism underlying perturbation of development when that expression pattern is disrupted.
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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 [48]
The organ-culture results (page not available) report that PU.1 expression induced a dendritic-cell marker and diverted thymocytes toward that lineage, but identify the affected DN1–DN2 cells as not yet committed to the T-cell lineage. The Discussion attributes diversion of committed DN3 cells to Spi-B, not PU.1. The paper does not establish that PU.1 re-expression in later committed pro-T cells activates myeloid genes or produces macrophages or promyelocytic-like cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInstead 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 [48]
The section on stage-dependent effects reports that Spi-B-transduced, T-lineage-committed DN3 thymocytes up-regulated a dendritic-cell marker, consistent with diversion to the dendritic-cell lineage. But it also reports that some re-expressed CD44 and reverted to a DN2 phenotype, so it does not establish diversion *instead of* reacquiring progenitor-like features. The paper does not report diversion to a macrophage program. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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“Instead of re-acquiring aspects of a progenitor-like state, the cells appear to transdifferentiate to a dendritic-cell or macrophage developmental program (48, 50, 58).”
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- Authors
- Lefebvre, J. M., Haks, M. C., Carleton, M. O., Rhodes, M., Sinnathamby, G., Simon, M. C., Eisenlohr, L. C., Garrett-Sinha, L. A., & Wiest, D. L.
- Affiliations
- Fox Chase Cancer Center (US)
- Immunobiology Working Group, Division of Basic Sciences, Fox Chase Cancer Center , Philadelphia, PA 19111
- Thomas Jefferson University (US)
- Howard Hughes Medical Institute (US)
- Department of Biochemistry, State University of New York , Buffalo, NY 14214
- Corresponding author
- Rhodes, Michele
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-05
- Volume
- 174
- Issue
- 10
- Pages
- 6184-6194
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1500023054
- Cited by
- 60
- References
- 74
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 6
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- National Institutes of Health (50306, 5r29ca073656-03, P01 CA06927)
- National Cancer Institute (P01 CA06927, CA 73656, CA 87407)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK50306, P30DK050306)
- 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
- Spi-B, ETS transcription factors, T cell lineage commitment, T cell development, Egr transcription factors, pre-TCR signaling, dendritic cell differentiation, thymic selection
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Dendritic Cells, DNA-Binding Proteins, Humans, Mice, Inbred C57BL, Organ Culture Techniques, Proto-Oncogene Proteins, Thymoma, Thymus Gland, Thymus Neoplasms, Transcription Factors, Transduction, Genetic, Trans-Activators, Down-Regulation, T-Lymphocyte Subsets, Mice, SCID, Mice, Knockout, Cell Lineage, Genes, T-Cell Receptor beta, Cell Line, Tumor, Fetal Development, Mice
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