Age- and tissue-dependent diversity of human plasmacytoid dendritic cells uncovers a cycling subset dominant in early life and cancer.

Plasmacytoid dendritic cells (pDCs) are innate sentinels that produce type I interferons (IFN-I) during infection. Here, we asked 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 revealed tissue-enriched programs, including IFN-I-imprinted pDCs in the thymus, NF-κB-imprinted pDCs in tonsils, and resting pDCs in blood and lymph nodes. Across tissues, we identified a pDC subset characterized by prostaglandin D2 production and dopamine responsiveness, indicating a potential neuromodulatory axis. Cycling pDCs were abundant in fetal and infant lymphoid tissues and declined with age, while remaining enriched in bone marrow (BM) throughout life. Blastic pDC neoplasm was associated with enrichment of cycling, mutation-bearing pDCs in the BM, suggesting that this niche serves as a reservoir for malignant pDCs. Thus, early in life, pDCs are generated within various lymphoid tissues. This tissue-specific hematopoiesis may result in distinct cellular and functional outputs.