Plasmacytoid Dendritic Cells Exhibit High Transferrin Receptor Expression Without Iron Accumulation

Area of Science:

• Immunology
• Cell Biology
• Proteomics

Background:

• Plasmacytoid dendritic cells (pDCs) are crucial for antiviral immunity via type I interferon (IFN-I) production.
• The proteomic and metabolic landscape of pDCs, especially their iron handling, is not fully understood.

Purpose of the Study:

• To define the steady-state proteome and iron metabolism of murine and human pDCs.
• To compare pDC proteomic organization with other dendritic cell subsets.
• To investigate the role of iron availability in pDC antiviral functions.

Main Methods:

• Deep, absolute quantitative mass spectrometry for proteomic analysis.
• Proteome-wide iron mapping and functional assays.
• Comparison of murine splenic pDCs with conventional dendritic cells and human pDCs.

Main Results:

• pDCs exhibit a conserved proteomic architecture across species with distinct metabolic features.
• High transferrin receptor (TFRC) expression drives robust iron uptake in pDCs.
• Iron is preferentially allocated to iron-sulfur and heme proteins, particularly in mitochondria, with balanced import/efflux.
• Iron availability does not limit TLR9-induced IFN-I or TNF production in pDCs.

Conclusions:

• pDCs possess a unique iron-handling program characterized by high TFRC, balanced iron flux, and targeted iron distribution.
• This program supports pDC function without iron limitation impacting antiviral cytokine production.