PSM Peptides From Community-Associated Methicillin-Resistant Staphylococcus aureus Impair the Adaptive Immune Response via Modulation of Dendritic Cell Subsets in vivo

Abstract

Dendritic cells (DCs) are key players of the immune system and thus a target for immune evasion by pathogens. We recently showed that the virulence factors phenol-soluble-modulins (PSMs) produced by community-associated methicillin-resistant <i>Staphylococcus aureus</i> (CA-MRSA) strains induce tolerogenic DCs upon Toll-like receptor activation via the p38-CREB-IL-10 pathway <i>in vitro</i>. Here, we addressed the hypothesis that <i>S. aureus</i> PSMs disturb the adaptive immune response via modulation of DC subsets <i>in vivo</i>. Using a systemic mouse infection model we found that <i>S. aureus</i> reduced the numbers of splenic DC subsets, mainly CD4⁺ and CD8⁺ DCs independently of PSM secretion. <i>S. aureus</i> infection induced upregulation of the C-C motif chemokine receptor 7 (CCR7) on the surface of all DC subsets, on CD4⁺ DCs in a PSM-dependent manner, together with increased expression of MHCII, CD86, CD80, CD40, and the co-inhibitory molecule PD-L2, with only minor effects of PSMs. Moreover, PSMs increased IL-10 production in the spleen and impaired TNF production by CD4⁺ DCs. Besides, <i>S. aureus</i> PSMs reduced the number of CD4⁺ T cells in the spleen, whereas CD4⁺CD25⁺Foxp3⁺ regulatory T cells (T_regs) were increased. In contrast, Th1 and Th17 priming and IFN-γ production by CD8⁺ T cells were impaired by <i>S. aureus</i> PSMs. Thus, PSMs from highly virulent <i>S. aureus</i> strains modulate the adaptive immune response in the direction of tolerance by affecting DC functions.