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-L1CD80) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1CD80) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1CD80) 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.

Background: Glucosidase II is an endoplasmic reticulum enzyme involved in quality control of glycoprotein folding. Results: The structure of the lectin domain of GII was determined by NMR spectroscopy. Conclusion: GII lectin domain structure contains a unique Trp residue critical for GII activity. Significance: GII␤ MRH domain structure is the first determined of an MRH domain present in a protein with enzymatic activity.