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237: Human BDCA2+ BDCA3int dendritic cells are a novel functional subtype of classical plasmacytoid dendritic cell

CYTOKINE(2013)

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Abstract
Dendritic cells (DCs) are a heterogeneous cell population critical in regulating immune responses to pathogens and self-antigens. Human peripheral blood DCs have been broadly characterized as plasmacytoid DC (BDCA2 + ), myeloid DC1 (BDCA1 + ) and myeloid DC2 (BDCA3 + ) subsets. Our study aimed to understand whether BDCA3 + DCs from human peripheral blood, the putative functional equivalent to murine CD8a + DCs, constitute a homogeneous population of myeloid DC2 or if there are BDCA2 + BDCA3 + DCs that are functionally related to pDC. We constructed multi-color panels to phenotype lineage neg PBMC for expression of BDCA2 and BDCA3 by flow cytometric analysis. Three different lineage neg DC subsets from the total circulating PBMC were observed: BDCA2 + /3 neg (∼0.21%), BDCA2 + /3 int (∼0.22%), and BDCA2 neg /3 int/hi (∼0.17%). To assess the functional significance of the BDCA2 + /3 int DCs, we stimulated PBMC with TLR9 agonists CpG-A or HSV-1 and stained for intracellular IFN-a and TNF-a in cells expressing BDCA2 and/or BDCA3. At 6hrs, the stimulated BDCA2 + /3 int DC subset yielded more IFN-a + and TNF-a + cells than the other 2 subsets. By 8hrs, the % IFN-a + was similarly higher for BDCA2 + /3 − and BDCA2 + /3 int DC subsets than for BDCA2 − /3 int/hi DCs. All three DC subsets produced IFN-l1/3 upon 8hr HSV-1 stimulation, but more of the BDCA2 + /3 − and BDCA2 + /3 int DCs expressed IFN-l1/3 than BDCA2 − /3 int/hi DCs. IRF7, the master regulatory transcription factor of IFN production in pDCs, was constitutively expressed by the BDCA2 + /3 neg and BDCA2 + /3 int subsets but not by the BDCA2 neg subset. Uptake (“nibbling”) of cell-associated membrane from live virus-infected cells induces pDCs to produce IFN-a and mature. Both BDCA2 + /3 neg and BDCA2 + /3 int DCs preferentially nibbled HSV-infected Raji cells (with nibbling by BDCA2 + /3 int > BDCA2 + /3 neg DCs), while the BDCA2 neg /3 int/hi DC subset efficiently nibbled both uninfected and infected cells to a similar extent. Together, these results suggest that BDCA2 + /3 int DCs exhibit major functions associated with classical pDCs and are phenotypically and functionally distinct from BDCA2 neg /3 int/hi DCs.
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