Staphylococcus aureus Protein A Triggers T Cell-Independent B Cell Proliferation by Sensitizing B Cells for TLR2 Ligands

Abstract

B cells possess functional characteristics of innate immune cells, as they can present Ag to T cells and can be stimulated with microbial molecules such as TLR ligands. Because crude preparations of Staphylococcus aureus are frequently used as polyclonal B cell activators and contain potent TLR2 activity, the scope of this study was to analyze the impact of S. aureus-derived TLR2-active substances on human B cell activation. Peripheral B cells stimulated with chemically modified S. aureus cell wall preparations proliferated in response to stimulation with crude cell wall preparations but failed to be activated with pure peptidoglycan, indicating that cell wall molecules other than peptidoglycan are responsible for B cell proliferation. Subsequent analysis revealed that surface protein A (SpA), similar to BCR cross-linking with anti-human Ig, sensitizes B cells for the recognition of cell wall-associated TLR2-active lipopeptides (LP). In marked contrast to TLR7- and TLR9-triggered B cell stimulation, stimulation with TLR2-active LP and SpA or with crude cell wall preparations failed to induce IgM secretion, thereby revealing qualitative differences in TLR2 signaling compared with TLR7/9 signaling. Notably, combined stimulation with SpA plus TLR2 ligands induced vigorous proliferation of a defined B cell subset that expressed intracellular IgM in the presence of IL-2. Conclusion: S. aureus triggers B cell activation via SpA-induced sensitization of B cells for TLR2-active LP. Combined SpA and TLR2-mediated B cell activation promotes B cell proliferation but fails to induce polyclonal IgM secretion as seen after TLR7 and TLR9 ligation.

Superantigen- and TLR-Dependent Activation of Tonsillar B Cells after Receptor-Mediated Endocytosis

“…However, MID stimulation alone is not enough to drive B cells into IgM secretion (37,52). Data from Bekeredjian-Ding et al (53) have suggested a synergy in B cell activation between the Staphylococcus aureus B cell superantigen protein A (SpA) and TLR2 signaling. However, SpA and TLR2 signaling is not sufficient to induce IgM production, as seen with SpA-expressing bacteria (45) or rSpA with either ligands directed against TLR7 or TLR9.…”

Staphylococcus aureus-Induced Plasmacytoid Dendritic Cell Activation Is Based on an IgG-Mediated Memory Response

“…One characteristic of this Gram-positive bacterium is its very potent TLR2 activity that is mediated by membrane-anchored LP and can be easily detected in TLR2-transfected HEK293 cells (data not shown and Ref. 46). TLR2-active LP have, in fact, been proposed to represent its major immune stimulatory component (46 -48).…”

“…To do so, we chose different approaches. First, we compared two well-described S. aureus reference strains: Cowan I (SAC), a high producer of SpA, and Wood 46, a strain deficient in SpA protein expression due to a sigB deficiency (46,49,50). Both strains were comparable in regards to their IFN-␣ triggering potential ( Fig.…”

Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells

“…1). Ag encounter as simulated through BCR cross-linking has been reported to increase the sensitivity of B cell responses to several microbial ligands (36,48,49). To investigate the impact of BCR cross-linking on responses elicited by these TLR ligands, B cell proliferation was measured in the presence or absence of total anti-Ig.…”