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Regulatory T Cells Functions and Increase In Vitro Priming of Modulin Peptides Modulate Dendritic Cell Phenol-Soluble Staphylococcus aureus

The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus depends on phenol-soluble modulin (PSM) peptide toxins, which are known to attract and lyse neutrophils. However, their influences on other immune cells remain elusive. In this study, we analyzed the impact of PSMs on dendritic cells (DCs) playing an essential role in linking innate and adaptive immunity. In human neutrophils, PSMs exert their function by binding to the formyl peptide receptor (FPR) 2. We show that mouse DCs express the FPR2 homolog mFPR2 as well as its paralog mFPR1 and that PSMs are chemoattractants for DCs at noncytotoxic concentrations. PSMs reduced clathrin-mediated endocytosis and inhibited TLR2 ligand-induced secretion of the proinflamma-tory cytokines TNF, IL-12, and IL-6, while inducing IL-10 secretion by DCs. As a consequence, treatment with PSMs impaired the capacity of DCs to induce activation and proliferation of CD4 + T cells, characterized by reduced Th1 but increased frequency of FOXP3 + regulatory T cells. These regulatory T cells secreted high amounts of IL-10, and their suppression capacity was dependent on IL-10 and TGF-b. Interestingly, the induction of tolerogenic DCs by PSMs appeared to be independent of mFPRs, as shown by experiments with mice lacking mFPR2 (mFPR2 2/2) and the cognate G protein (p110g 2/2). Thus, PSMs from highly virulent pathogens affect DC functions, thereby modulating the adaptive immune response and probably increasing the tolerance toward the pathogen. S taphylococcus aureus is a major cause of invasive infectious diseases ranging from skin and soft tissue infections to severe systemic infections such as endocarditis or sepsis (1). The increasing prevalence of methicillin-resistant S. aureus strains, being highly resistant to antibiotic treatment, has become a significant public health threat (2). Whereas methicillin-resistant S. aureus strains used to be restricted to hospital settings, there was a dramatic spread in the last decade of new community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300, causing severe infections also in healthy individuals (3). Several virulence factors contribute to the pathoge-nicity of CA-MRSA, including a-hemolysin, Panton-Valentine leukocidin, and phenol-soluble modulin (PSM) peptides (4–7). PSMs play essential roles in the virulence of CA-MRSA, as they are strongly expressed in CA-MRSA strains and knockout of these peptides leads to loss of CA-MRSA virulence (6). This group of virulence factors consists of four PSMa peptides (PSMa1–4), two PSMb peptides (PSMb1–2), and the long-known d-toxin, …