A Modulatory Interleukin-10 Response to Staphylococcal Peptidoglycan Prevents Th1/Th17 Adaptive Immunity to Staphylococcus aureus

Toll-like receptor (TLR) 2 on antigen-presenting cells (APCs) enables these cells to recognize peptidoglycanembedded lipopeptides and glycopolymers in the Staphylococcus aureus cell wall and mount an inflammatory response to this microbe. TLR2 signalling can also modulate immunity to S. aureus by inducing an interleukin (IL)‐10 response in APCs. What determines the balance between proinflammatory and modulatory responses to S. aureus is unknown. We show that the modulatory IL-10 response preferentially occurs upon CD14- and CD36-independent TLR2 signaling, triggering PI3K activation, and is restricted to monocytes and monocytederived macrophages (MUs). In contrast, monocyte-derived dendritic cells (DCs) produce mostly IL-12 and IL-23. The differential APC polarization induced by staphylococcal peptidoglycan translates into differential T helper responses: MUs primarily trigger IL-10 and weak IL-17 responses, whereas DCs trigger a robust Th1/ Th17 response. Exploitation of TLR2 signalling plasticity by S. aureus may explain the wide range of outcomes of human encounters with this microbe. Staphylococcus aureus is a Gram-positive bacterium present in the nostrils, upper respiratory tract, and skin of up to two-thirds of human beings without causing any apparent disease. S. aureus is also one of the most common pathogens isolated from clinical specimens causing skin and respiratory infections and invasive, distant site, and systemic infections, such as osteomyelitis, endocarditis, and sepsis. S. aureus can cause severe toxic shock through the release of pyrogenic exotoxins