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Derivation of T Cells In Vitro from Mouse Embryonic Stem Cells
Published on: October 14, 2014
Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells
D Allman1, F G Karnell, J A Punt
1Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
The Journal of Experimental Medicine
|July 4, 2001
Summary
Notch1 signaling drives T cell commitment from progenitor cells. However, T cell receptor signaling is essential for the expansion and subsequent leukemic transformation of these developing T cells.
Area of Science:
- Immunology
- Developmental Biology
- Hematopoiesis
Background:
- Notch1 signaling is crucial for T cell development.
- Previous studies showed dominant active Notch1 (ICN1) in hematopoietic stem cells (HSCs) induces thymic-independent T cell development in bone marrow (BM).
Purpose of the Study:
- To investigate Notch1's role in early T cell development and extrathymic T lineage commitment.
- To determine the dependence of ICN1-induced T cell development on pre-T cell receptor (TCR) signaling.
Main Methods:
- Transduction of HSCs with ICN1 transgene.
- Repopulation of mice with transduced HSCs from various genetic backgrounds (Rag-2(-/-), SLP-76(-/-)).
- Analysis of novel BM cell populations expressing CD3 epsilon, pre-T alpha mRNA, CD44, and CD25.
Main Results:
- ICN1-transduced HSCs from Rag-2(-/-) or SLP-76(-/-) mice failed to develop double-positive (DP) BM cells.
- ICN1-transduced Rag-2(-/-) progenitors generated novel BM populations indicating pre-DP T cell development.
- Restoration of TCR beta in Rag-2(-/-) mice enabled ICN1-induced DP development, leading to T cell leukemia.
Conclusions:
- Notch signaling directs T lineage commitment from multipotent progenitor cells.
- Expansion and leukemic transformation of ICN1-induced T cells require T cell-specific signals, particularly TCR signaling.
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