Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.
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DOI：
10.1084/jem.20170298
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发表时间：
2018-02-05
期刊：
影响因子：
--
通讯作者：
Phipps S
中科院分区：
文献类型：
--
作者：
Lynch JP;Werder RB;Loh Z;Sikder MAA;Curren B;Zhang V;Rogers MJ;Lane K;Simpson J;Mazzone SB;Spann K;Hayball J;Diener K;Everard ML;Blyth CC;Forstner C;Dennis PG;Murtaza N;Morrison M;Ó Cuív P;Zhang P;Haque A;Hill GR;Sly PD;Upham JW;Phipps S
Lynch等人提供了rsv -细支气管炎与哮喘发展之间因果关系的证据，并强调了一种常见但与年龄相关的sema4a介导途径，通过该途径，pDCs和微生物定植诱导T细胞扩增，从而赋予对严重细支气管炎和哮喘的保护作用。呼吸道合胞病毒-细支气管炎是继发哮喘的主要独立危险因素，但其病因机制尚不清楚。我们发现，仅在原发性肺炎病毒感染期间，短暂性浆细胞样树突状细胞（pDC）耗竭易在早期发生严重的细支气管炎，并在再次感染后的晚年发生哮喘。pDC耗竭可减少干扰素的产生并增加病毒载量；然而，在缺乏pdc来源的信号蛋白4a （Sema4a）的情况下，免疫病理的升高和对随后哮喘的易感性源于功能性神经匹林-1+调节性T （T reg）细胞的扩增失败。在成年小鼠中，pDC耗竭仅在抗生素治疗后才易患严重的细支气管炎。与微生物组的保护作用一致，用微生物衍生的代谢物丙酸酯治疗pdc耗竭的新生儿可促进sema4a依赖性T细胞扩增，从而改善两种疾病。在患有病毒性细支气管炎的儿童中，鼻丙酸水平降低并与il -6高/ il - 100低微环境相关。我们强调了一种常见但与年龄相关的sema4a介导途径，通过该途径，pDCs和微生物定植诱导T细胞扩增，以预防严重毛细支气管炎和随后的哮喘。
Lynch et al. provide evidence of a causal relationship between RSV-bronchiolitis and asthma development and highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to confer protection against severe bronchiolitis and asthma. 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-6high/IL-10low 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.
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