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<p>Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.</p>

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TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Rebeca Arroyo Hornero,
  • Raul A. Maqueda-Alfaro,
  • Miguel A. Solís-Barbosa,
  • Rebecca A. Leylek,
  • Olin Medina Chavez,
  • Olivia M. Martinez,
  • Andres Gottfried-Blackmore,
  • Juliana Idoyaga

摘要

Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.