Diversification of human plasmacytoid predendritic cells in response to a single stimulus

Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1(+)CD80(-)) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80(+)) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1(+)CD80(+)) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding-and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.