The host must develop tolerance to commensal microbes and protective responses to infectious pathogens, yet the mechanisms enabling a privileged relationship with commensals remain largely unknown. Skin colonization by commensal Staphylococcus epidermidis facilitates immune tolerance preferentially in neonates via induction of antigen-specific regulatory T cells (Tregs). Here, we demonstrate that this tolerance is not indiscriminately extended to all bacteria encountered in this early window. Rather, neonatal colonization by Staphylococcus aureus minimally enriches for antigen-specific Tregs and does not prevent skin inflammation upon later-life exposure. S. aureus α-toxin contributes to this response by stimulating myeloid cell production of IL-1β, which limits S. aureus-specific Tregs. Loss of α-toxin or the IL-1 receptor increases Treg enrichment, whereas topical application of IL-1β or α-toxin diminishes tolerogenic responses to S. epidermidis. Thus, the preferential activation of a key alarmin pathway facilitates early discrimination of microbial "foe" from "friend," thereby preventing tolerance to a common skin pathogen.
Keywords: IL-1; commensal; dendritic cells; neonatal; pathogen; regulatory T cells; skin bacteria; skin immunity; staphylococcus.
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