Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway
Abstract
Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were identified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin−Sca-1+Kit+CD27−) and multipotent progenitors (Lin−Sca-1+Kit+CD27+), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification. Bcl11b was uniquely T lineage restricted and induced by Notch/Delta signaling specifically upon entry into the T lineage differentiation pathway.
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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 [32]
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- Authors
- Tydell, C. C., David-Fung, E.-S., Moore, J. E., Rowen, L., Taghon, T., & Rothenberg, E. V.
- Affiliations
- California Institute of Technology (US)
- Division of Biology, California Institute of Technology , Pasadena, CA 91125
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-07-01
- Volume
- 179
- Issue
- 1
- Pages
- 421-438
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1570366622
- Cited by
- 99
- References
- 7
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 2 · 2014: 6 · 2013: 7 · 2012: 7
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- National Cancer Institute (R01CA98925, R01CA90233, R01CA090233, R01CA098925)
- National Institute of Allergy and Infectious Diseases (F32AI068366, K08AI054699)
- 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 development, Notch signaling, Delta-Notch signaling, BCL11B, TCF1, Deltex1, FKBP5, multipotent progenitors, transcription factors, double-negative thymocytes
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Fetus, Hematopoietic Stem Cells, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Repressor Proteins, Thymus Gland, Signal Transduction, Up-Regulation, T-Lymphocyte Subsets, Mice, SCID, Coculture Techniques, Cell Lineage, Gene Expression Profiling, Tumor Suppressor Proteins, Lymphopoiesis, Intracellular Signaling Peptides and Proteins, Mice, Receptors, Notch
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