Laboratoire d'Immunothérapie, Institut Pasteur, Paris, France.
J Immunol. 2010 Jan 15;184(2):1062-70. doi: 10.4049/jimmunol.0901822. Epub 2009 Dec 9.
We have previously shown that bacillus Calmette-Guérin (BCG) inactivated by extended freeze-drying (EFD) reduces airway hyperresponsiveness, whereas live and heat-killed BCG fail to do so. However, the cells involved in the protective effect and the signaling and transcriptional networks that could reprogram T cell commitment after EFD BCG treatment remained to be elucidated. We investigated whether EFD BCG targets plasmacytoid dendritic cells (pDCs) potentially involved in the polarization of regulatory T cells (Tregs) and the transcriptional factors that regulate allergic inflammation. OVA-sensitized mice were s.c. injected with EFD, live, or heat-killed BCG. We analyzed after the injection of the various BCG preparations: 1) pDCs recruited in the draining lymph nodes (day 4); 2) transcription factors involved in inflammation and T cell commitment in spleen and lungs after OVA challenge (day 28). Airway hyperresponsiveness and transcription factors were determined after in vivo depletion of pDCs or Tregs in EFD BCG-treated and OVA-challenged mice. EFD BCG reduced inflammation via the recruitment of pDCs polarizing the differentiation of naive CD4+ T lymphocytes into Tregs. In vivo, pDC or Treg depletion at the time of EFD BCG treatment abrogated the protection against inflammation. EFD BCG treatment upregulated Forkhead-winged helix transcription factor (Treg signature) and downregulated GATA-3 and RORgammat (Th2 and Th17 signatures) more efficiently than live and heat-killed BCG. Moreover, only EFD BCG enhanced peroxisome proliferator-activated receptor gamma expression and blocked NF-kappaB activation, cyclooxygenase expression, and p38 MAPK phosphorylation. EFD BCG reduced allergic inflammation by recruiting pDCs that promoted Tregs; EFD BCG acted as a peroxisome proliferator-activated receptor gamma agonist and thus could be used in asthma and other inflammatory diseases.
我们之前已经表明，通过延长冻干（EFD）失活的卡介苗（BCG）可降低气道高反应性，而活的和热杀死的 BCG 则不能。然而，参与保护作用的细胞以及可以在 EFD BCG 处理后重新编程 T 细胞承诺的信号和转录网络仍有待阐明。我们研究了 EFD BCG 是否针对浆细胞样树突状细胞（pDCs），这些细胞可能参与调节性 T 细胞（Tregs）的极化和调节过敏炎症的转录因子。OVA 致敏的小鼠通过皮下注射 EFD、活的或热杀死的 BCG。在注射各种 BCG 制剂后，我们分析了：1）引流淋巴结中募集的 pDCs（第 4 天）；2）OVA 挑战后脾脏和肺部中参与炎症和 T 细胞承诺的转录因子（第 28 天）。在 EFD BCG 处理和 OVA 挑战的小鼠中体内耗尽 pDCs 或 Tregs 后，测定气道高反应性和转录因子。EFD BCG 通过募集 pDCs 来减少炎症，这些 pDCs 可将幼稚 CD4+T 淋巴细胞分化为 Tregs。在体内，在 EFD BCG 处理时耗尽 pDC 或 Treg 会破坏对炎症的保护。EFD BCG 治疗可更有效地上调叉头翼状螺旋转录因子（Treg 特征），下调 GATA-3 和 RORgammat（Th2 和 Th17 特征），而活的和热杀死的 BCG 则不能。此外，只有 EFD BCG 可增强过氧化物酶体增殖物激活受体 γ 的表达并阻断 NF-kappaB 激活，环氧化酶表达和 p38 MAPK 磷酸化。EFD BCG 通过募集促进 Tregs 的 pDCs 来减少过敏炎症；EFD BCG 作为过氧化物酶体增殖物激活受体 γ 激动剂，因此可用于哮喘和其他炎症性疾病。
