Age- and tissue-dependent diversity of human plasmacytoid dendritic cells uncovers a cycling subset dominant in early life and cancer — ASN Events
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Age- and tissue-dependent diversity of human plasmacytoid dendritic cells uncovers a cycling subset dominant in early life and cancer (#118)

Alina Ulezko Antonova 1 , Patrick Fernandes Rodrigues 2 , Chelsea Mannie 1 , Giorgia Ferrari 3 , Horacio Carvajal Dominguez 1 , Mattia Buggati 4 , William Vermi 4 , Tong Wu 1 , Marina Cella 5 , Pirooz Eghtesady 1 , Marco Colonna 1
  1. Washington University School of Medicine in St. Louis, Saint Louis, MISSOURI, United States
  2. Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland
  3. Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States
  4. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
  5. Broad Institute of MIT and Harvard, Cambridge, Massachussets, USA

Plasmacytoid dendritic cells (pDCs) are innate sentinels that produce type I interferons (IFN-I) during infection. Here, we ask how developmental stage and tissue context shape human pDC transcriptional states. Single-cell RNA sequencing of pDCs from blood, thymus, lymph nodes, and tonsils across fetal, infant, and pediatric stages reveals tissue-enriched programs, including IFN-I–imprinted pDCs in thymus, NFκB-imprinted pDCs in tonsils, and resting pDCs in blood and lymph nodes. Across tissues, we identify a conserved pDC subset characterized by prostaglandin D2 production and dopamine responsiveness, indicating a potential neuromodulatory axis. Cycling pDCs are abundant in fetal and infant lymphoid tissues and decline with age, while remaining enriched in bone marrow throughout life. Blastic pDC neoplasm is associated with enrichment of cycling, mutation-bearing pDCs in bone marrow, suggesting this niche serves as a reservoir for malignant pDCs. These findings define developmentally regulated and tissue-imprinted pDC programs that shape immune homeostasis and disease.