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Interferon priming is essential for human CD34+ cell-derived plasmacytoid dendritic cell maturation and function.

A Laustsen1, R O Bak1,2,3, C Krapp1

  • 1Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, 8000, Aarhus C, Denmark.

Nature Communications
|September 1, 2018
PubMed
Summary

Generating plasmacytoid dendritic cells (pDCs) from hematopoietic stem cells (HSCs) is possible. Priming with interferons (IFNs) enhances their function, enabling the creation of gene-modified pDCs for research.

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Area of Science:

  • Immunology
  • Cell Biology
  • Hematopoiesis

Background:

  • Plasmacytoid dendritic cells (pDCs) are crucial for immune responses.
  • Understanding pDC development and function is key to immune competence.

Purpose of the Study:

  • To investigate the differentiation and functional maturation of pDC precursors derived from human CD34+ hematopoietic stem and progenitor cells (HSPCs).
  • To explore the role of interferons (IFNs) in pDC maturation and to establish methods for generating gene-modified pDCs.

Main Methods:

  • Differentiation of pDC precursors from human CD34+ HSPCs.
  • Stimulation with Toll-like receptor (TLR) agonists, cGAS, and RIG-I agonists.
  • Priming with type I and II IFNs.
  • CRISPR/Cas9 genome editing of HSPCs.
  • Analysis of pDC marker expression, cytokine induction (IFN, IL-6), and receptor function.

Main Results:

  • HSPC-derived pDC precursors exhibit low surface marker expression and limited responses to TLR7/9 agonists, but not cGAS/RIG-I agonists.
  • Priming with type I and II IFNs successfully induced a mature pDC phenotype and function.
  • CRISPR/Cas9 editing demonstrated that IFN-α receptor expression is essential for optimal function but not differentiation of precursor pDCs.
  • Successful generation of gene-modified human pDCs from HSPCs.

Conclusions:

  • Interferons play a critical role in regulating the functional maturation of pDC precursors.
  • This study provides a method for generating functional, gene-modified human pDCs from HSPCs.
  • These findings advance the potential for using engineered pDCs in immunological research and therapeutic applications.