BDCA2-dependent phagocytosis enables strain-specific activation of plasmacytoid dendritic cells by lactic acid bacteria

Plasmacytoid dendritic cells (pDCs) detect microbial DNA via endosomal Toll-like receptor 9 (TLR9), yet the mechanisms by which they selectively internalize specific bacteria remain unclear. We demonstrate that type I interferon (IFN-I) responses to lactic acid bacteria (LAB) are entirely dependent on phagocytosis and exhibit pronounced strain specificity. Among tested strains, Lactococcus lactis strain Plasma (LC-Plasma) was efficiently phagocytosed and potently induced IFN-α in both primary human pDCs and CAL-1 cells, whereas closely related strains showed minimal uptake and cytokine production. Phagocytosis was essential for TLR9-dependent IFN-α secretion. Transcriptomic and functional analyses identified BDCA2, a galactose-binding C-type lectin receptor, as a key mediator of LAB uptake. Blocking BDCA2 significantly impaired both phagocytosis and cytokine responses. BDCA2-Fc fusion proteins bound strongly to LAB. Glycan profiling identified glycan signatures associated with highly phagocytosed Lactococcus strains. These findings define BDCA2-dependent phagocytosis as a critical determinant of strain-specific LAB recognition by human pDCs.