Abstract
The development of T cells from multipotent progenitors in the thymus occurs by cascades of interactions between signaling molecules and transcription factors, resulting in the loss of alternative lineage potential and the acquisition of the T-cell functional identity. These processes require Notch signaling and the activity of GATA3, TCF1, Bcl11b, and the E-proteins HEB and E2A. We have shown that HEB factors are required to inhibit the thymic NK cell fate and that HEBAlt allows the passage of T-cell precursors from the DN to DP stage but is insufficient for suppression of the NK cell lineage choice. HEB factors are also required to enforce the death of cells that have not rearranged their TCR genes. The synergistic interactions between Notch1, HEBAlt, HEBCan, GATA3, and TCF1 are presented in a gene network model, and the influence of thymic stromal architecture on lineage choice in the thymus is discussed.
Highlights
T-Cell Progenitors and Lineage PlasticityPluripotent progenitors are sequentially restricted in lineage potential and progressively committed to a single lineage choice
The development of T cells from multipotent progenitors in the thymus occurs by cascades of interactions between signaling molecules and transcription factors, resulting in the loss of alternative lineage potential and the acquisition of the T-cell functional identity
We have shown that HEB factors are required to inhibit the thymic natural killer (NK) cell fate and that HEBAlt allows the passage of T-cell precursors from the DN to DP stage but is insufficient for suppression of the NK cell lineage choice
Summary
Pluripotent progenitors are sequentially restricted in lineage potential and progressively committed to a single lineage choice. The thymus, a site where T cells are generated, does not produce stem cells, and the generation of T cells depends solely on the intermittent input of progenitors from adult bone marrow [2]. The DN1c, DN1d, and DN1e subsets have been shown to have the potential to generate dendritic cells (DCs) in the thymus [5, 6]. ETPs have the potential to generate myeloid cells in Clinical and Developmental Immunology the thymus [8]. These studies indicate that B-cell potential is lost before myeloid potential in T-cell precursors prior to T-lineage commitment
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