Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1⁺ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6^high/IL-10^low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.

呼吸道合胞病毒-毛细支气管炎是随后发生哮喘的主要独立危险因素，但其致病机制仍不清楚。我们发现，仅在原发性肺炎病毒感染期间短暂的浆细胞样树突状细胞（pDC）耗竭，在早期感染时易患严重的细支气管炎，而在再次感染后的后期生活中则易患哮喘。pDC消耗减少了干扰素的产生并增加了病毒载量；然而，由于无法扩展功能性神经pilin-1 ^+而导致的免疫病理学和对随后哮喘的易感性增强在没有pDC衍生的信号量4a（Sema4a）的情况下，调节性T（T reg）细胞。在成年小鼠中，仅在抗生素治疗后，pDC耗尽才易患严重的毛细支气管炎。与对微生物组的保护作用一致，用微生物衍生的代谢产物丙酸酯治疗pDC贫血的新生儿可促进依赖Sema4a的T reg细胞扩增，从而改善两种疾病。在患有病毒性毛细支气管炎的儿童中，丙酸水平降低，并且与IL-6^高/ IL-10^低微环境相关。我们强调了一个常见但与年龄有关的Sema4a介导的途径，通过该途径pDC和微生物定植诱导T reg细胞扩增，以预防严重的细支气管炎和随后的哮喘。