Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Immunity. 2019 Jan 15;50(1):225-240.e4. doi: 10.1016/j.immuni.2018.11.012. Epub 2019 Jan 8.
Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.
婴儿比成人更容易患过敏性哮喘。然而，其潜在的机制尚不清楚。我们在这里表明，在低剂量脂多糖（LPS）存在的情况下，用屋尘螨（HDM）致敏的小鼠可预防成年而非婴儿小鼠的 T 辅助 2（Th2）细胞过敏反应。从机制上讲，成年 CD11b 迁移树突状细胞（mDCs）响应肿瘤坏死因子-α（TNF-α）而上调转录因子 T 细胞因子（T-bet），这在 HDM+LPS 致敏后迅速诱导。因此，成年 CD11b mDCs 产生白细胞介素 12（IL-12），通过促进反应性 T 细胞中 T-bet 的上调来阻止 Th2 细胞的发育。相反，婴儿在 HDM+LPS 致敏后未能诱导 TNF-α。因此，CD11b mDCs 未能上调 T-bet，也不能正常分泌 IL-12，因此 Th2 细胞反应在婴儿小鼠中正常发育。因此，TNF-α 的可用性决定了 CD11b mDC 在依赖于剂量的内毒素致敏时抑制过敏 Th2 细胞反应的能力，并且是控制婴儿小鼠对过敏性气道炎症易感性的关键介质。
