Pathogen-Triggered Activation of Plasmacytoid Dendritic Cells Induces IL-10–Producing B Cells in Response to Staphylococcus aureus

Abstract

Induction of polyclonal B cell activation is a phenomenon observed in many types of infection, but its immunological relevance is unclear. In this study we show that staphylococcal protein A induces T cell–independent human B cell proliferation by enabling uptake of TLR-stimulating nucleic acids via the VH3+ BCR. We further demonstrate that Staphylococcus aureus strains with high surface protein A expression concomitantly trigger activation of human plasmacytoid dendritic cells (pDC). Sensitivity to chloroquine, cathepsin B inhibition, and a G-rich inhibitory oligodeoxynucleotide supports the involvement of TLR9 in this context. We then identify pDC as essential cellular mediators of B cell proliferation and Ig production in response to surface protein A–bearing S. aureus. The in vivo relevancy of these findings is confirmed in a human PBMC Nod/scidPrkdc/γc−/− mouse model. Finally, we demonstrate that co-operation of pDC and B cells enhances B cell–derived IL-10 production, a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. IL-10 release is partially dependent on TLR2-active lipoproteins, a hallmark of the Staphylococcus species. Collectively, our data suggest that S. aureus exploits pDC and TLR to establish B cell–mediated immune tolerance.

Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence

“…IL-10 is a cytokine associated with immunosuppression and induction of IgG4, an isotype frequently dominating the IgG response to S. aureus. As IL-10 release is partially dependent on TLR2-active lipoproteins, they contribute directly or indirectly to B cell-mediated immune tolerance (82).…”

Plasmacytoid dendritic cell bactericidal activity against Burkholderia pseudomallei

“…*P 0.05 and **P 0.01 determined using a 2way ANOVA with post-hoc multiple comparisons. type I IFN responses to bacteria such as Staphylococcus aureus, other bacteria such as Streptococcus pyogenes, stimulate low type I IFN responses in human pDC similar that observed for B. pseudomallei-infected human pDC [14,24]. Interestingly, B. pseudomallei isolates of high and low virulence induced comparable type I IFN responses.…”

“…Increased MHC class II and CD86 expression on mature pDC is important for activation of naive T cells [20]. In some cases, pDC maturation responses are exploited to develop an inappropriate immune response that benefits the persistence of bacteria [14]. In this study, B. pseudomallei infection of murine pDC resulted in distinct differences in MHC class II and CD86 expression on BALB/c pDC and C57BL/6 pDC.…”

Uncoupling of Pro- and Anti-Inflammatory Properties of Staphylococcus aureus

“…This is in contrast to the IL-10 response to other MAMPs (25,(47)(48)(49). Monocytes/macrophages are early responders to S. aureus, and their phenotype would be highly influential in establishing the microenvironment that sets up subsequent adaptive responses.…”