Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7144
Spatially restricted JAG1-Notch signaling in human thymus provides suitable DC developmental niches
J Exp Med. 2017;6;214(11):3361-3379.
A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) resident in the steady-state thymus is whether early thymic progenitors (ETPs) could escape T cell fate constraints imposed normally by a Notch-inductive microenvironment and undergo DC development. By modeling DC generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated Notch signaling allows human ETPs to undertake a myeloid transcriptional program, resulting in GATA2-dependent generation of CD34+ CD123+ progenitors with restricted pDC, cDC, and monocyte potential, whereas Delta-like1 signaling down-regulates GATA2 and impairs myeloid development. Progressive commitment to the DC lineage also occurs intrathymically, as myeloid-primed CD123+ monocyte/DC and common DC progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. The identification of a discrete JAG1+ thymic medullary niche enriched for DC-lineage cells expressing Notch receptors further validates the human thymus as a DC-poietic organ, which provides selective microenvironments permissive for DC development.
Cell Dedifferentiation | Cell Lineage | Cells, Cultured | Dendritic Cells | GATA2 Transcription Factor | Gene Expression | Humans | Intercellular Signaling Peptides and Proteins | Interleukin-3 Receptor alpha Subunit | Jagged-1 Protein | Membrane Proteins | Microscopy, Confocal | Monocytes | Myeloid Cells | Receptors, Notch | T-Lymphocytes | Thymus Gland | Signal Transduction | Stem Cell Niche
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