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.

中文翻译：

---

毒素触发的白介素1受体信号转导可早期区分病原性皮肤细菌与普通皮肤细菌。

宿主必须发展对共生微生物的耐受性和对传染性病原体的保护性反应，然而，与共生微生物建立特权关系的机制仍然未知。通过表皮葡萄球菌的皮肤定植，可通过诱导抗原特异性调节性T细胞（Tregs）优先促进新生儿的免疫耐受。在这里，我们证明了这种耐受性并没有不加选择地扩展到在此早期窗口中遇到的所有细菌。而是，金黄色葡萄球菌对新生儿的定植可最小限度地富集抗原特异性Treg，并且在以后的生活中不能预防皮肤炎症。金黄色葡萄球菌α毒素通过刺激IL-1β的髓样细胞产生而促进了这种反应，这限制了金黄色葡萄球菌特异的Tregs。α-毒素或IL-1受体的丢失会增加Treg的富集，而局部应用IL-1β或α-毒素会减少对表皮葡萄球菌的致耐受性。因此，关键警报蛋白途径的优先激活促进了微生物“敌人”与“朋友”的早期区分，从而防止了对常见皮肤病原体的耐受性。