Plasmacytoid Dendritic Cells Exhibit High Transferrin Receptor Expression Without Iron Accumulation

TY - JOUR

T1 - Plasmacytoid Dendritic Cells Exhibit High Transferrin Receptor Expression Without Iron Accumulation

AU - Corkish, Carrie

AU - O'Shaughnessy, Simon

AU - Lin, Claire

AU - Wugk, Sophia

AU - Kenny, Sarah

AU - Sinclair, Linda

AU - Cloonan, Suzanne

AU - Finlay, David

N1 - Publisher Copyright: © 2026 The Author(s). European Journal of Immunology published by Wiley-VCH GmbH.

PY - 2026/6/17

Y1 - 2026/6/17

N2 - Plasmacytoid dendritic cells (pDCs) are specialized antiviral sentinels defined by rapid type I interferon (IFN‑I) production, yet their proteomic organization and metabolic requirements remain incompletely understood. We established the steady‑state proteome of murine splenic pDCs directly ex vivo using deep, absolute quantitative mass spectrometry and compared it with conventional dendritic cell subsets and human pDCs. pDCs exhibited a highly conserved proteomic architecture across species, with selective divergence in central carbon metabolism, amino‑acid utilization, and nutrient transporter expression. Notably, pDCs expressed exceptionally high levels of the transferrin receptor (TFRC) in both mice and humans and displayed robust transferrin‑mediated iron uptake relative to other splenic immune populations. Despite this, pDCs did not demonstrate increased total cellular iron or enhanced ferritin‑based storage. Instead, proteome‑wide iron mapping revealed preferential allocation of iron to functional iron-sulfur and heme‑containing proteins, particularly within mitochondrial pathways. Detection of the iron exporter ferroportin indicated coordinated iron import and efflux, establishing sustained iron flux rather than net accumulation. Functional assays showed that iron availability does not constrain TLR9‑induced IFN‑I or TNF production. Together, these data define a conserved iron‑handling program in pDCs characterized by high TFRC expression, balanced iron flux, and targeted redistribution into essential protein systems.

AB - Plasmacytoid dendritic cells (pDCs) are specialized antiviral sentinels defined by rapid type I interferon (IFN‑I) production, yet their proteomic organization and metabolic requirements remain incompletely understood. We established the steady‑state proteome of murine splenic pDCs directly ex vivo using deep, absolute quantitative mass spectrometry and compared it with conventional dendritic cell subsets and human pDCs. pDCs exhibited a highly conserved proteomic architecture across species, with selective divergence in central carbon metabolism, amino‑acid utilization, and nutrient transporter expression. Notably, pDCs expressed exceptionally high levels of the transferrin receptor (TFRC) in both mice and humans and displayed robust transferrin‑mediated iron uptake relative to other splenic immune populations. Despite this, pDCs did not demonstrate increased total cellular iron or enhanced ferritin‑based storage. Instead, proteome‑wide iron mapping revealed preferential allocation of iron to functional iron-sulfur and heme‑containing proteins, particularly within mitochondrial pathways. Detection of the iron exporter ferroportin indicated coordinated iron import and efflux, establishing sustained iron flux rather than net accumulation. Functional assays showed that iron availability does not constrain TLR9‑induced IFN‑I or TNF production. Together, these data define a conserved iron‑handling program in pDCs characterized by high TFRC expression, balanced iron flux, and targeted redistribution into essential protein systems.

KW - CD71

KW - dendritic cells

KW - interferons

KW - metabolism

KW - nutrient transport

KW - pDC

KW - plasmacytoid

KW - proteomics

KW - TFRC

KW - transferrin receptor

UR - https://www.scopus.com/pages/publications/105042166480

U2 - 10.1002/eji.70219

DO - 10.1002/eji.70219

M3 - Article

C2 - 42307014

AN - SCOPUS:105042166480

SN - 0014-2980

VL - 56

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 6

M1 - e70219

ER -