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Spatially restricted JAG1-Notch signaling in human thymus provides suitable DC developmental niches

Enrique Martín-Gayo1, Sara González-García1, María J García-León1

  • 1Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.

The Journal of Experimental Medicine
|September 27, 2017
PubMed

Insights

Notch signaling directs early thymic progenitors (ETPs) to develop into dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). This reveals the thymus as a site for DC development.

Area of Science:

  • Immunology
  • Developmental Biology
  • Cell Biology

Background:

  • The developmental origins of conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) in the thymus remain incompletely understood.
  • It is unclear if early thymic progenitors (ETPs) can bypass T cell development pathways to differentiate into DCs.

Purpose of the Study:

  • To investigate the role of Notch signaling in directing ETPs towards DC development within the thymus.
  • To identify specific progenitor populations and microenvironments involved in thymic DC generation.

Main Methods:

  • Modeling DC generation using bulk and clonal cultures of human thymic cells.
  • Analyzing the effects of Jagged1 (JAG1) and Delta-like1 Notch signaling on progenitor potential and gene expression (e.g., GATA2).
  • Characterizing thymic progenitor populations and identifying specific niches using cell surface markers (e.g., CD34, CD123, JAG1).

Main Results:

  • Jagged1-mediated Notch signaling promotes a myeloid transcriptional program in human ETPs, leading to GATA2-dependent generation of CD34+ CD123+ progenitors with DC and monocyte potential.
  • Delta-like1 signaling inhibits GATA2 expression and impairs myeloid development.
  • The human thymus harbors intrathymic progenitors committed to the DC lineage, including myeloid-primed CD123+ monocyte/DC and common DC progenitors.
  • A Jagged1+ thymic medullary niche enriched for Notch receptor-expressing DC-lineage cells supports DC development.

Conclusions:

  • The human thymus is a DC-poietic organ capable of generating cDCs and pDCs from ETPs.
  • Notch signaling, particularly via Jagged1, plays a critical role in directing thymic progenitors towards DC differentiation.
  • Specific thymic microenvironments provide essential signals for intrathymic DC development.

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