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Development. 2018 Aug 13;145(16). pii: dev165597. doi: 10.1242/dev.165597.

Dynamic regulation of NOTCH1 activation and Notch ligand expression in human thymus development.

Author information

1
Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Consejo de Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain.
2
Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
3
CIBER CV, 28029 Madrid, Spain.
4
Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, Consejo de Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain mtoribio@cbm.csic.es.

Abstract

T-cell development is a complex dynamic process that relies on ordered stromal signals delivered to thymus-seeding progenitors that migrate throughout different thymus microenvironments (TMEs). Particularly, Notch signaling provided by thymic epithelial cells (TECs) is crucial for T-cell fate specification and generation of mature T cells. Four canonical Notch ligands (Dll1, Dll4, Jag1 and Jag2) are expressed in the thymus, but their spatial distribution in functional TMEs is largely unknown, especially in humans, and their impact on Notch1 activation during T-lymphopoiesis remains undefined. Based on immunohistochemistry and quantitative confocal microscopy of fetal, postnatal and adult human and mouse thymus samples, we show that spatial regulation of Notch ligand expression defines discrete Notch signaling niches and dynamic species-specific TMEs. We further show that Notch ligand expression, particularly DLL4, is tightly regulated in cortical TECs during human thymus ontogeny and involution. Also, we provide the first evidence that NOTCH1 activation is induced in vivo in CD34+ progenitors and developing thymocytes at particular cortical niches of the human fetal and postnatal thymus. Collectively, our results show that human thymopoiesis involves complex spatiotemporal regulation of Notch ligand expression, which ensures the coordinated delivery of niche-specific NOTCH1 signals required for dynamic T-cell development.

KEYWORDS:

Human; Notch ligands; Thymus microenvironment; γδ T cells

PMID:
30042180
DOI:
10.1242/dev.165597
[Indexed for MEDLINE]
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