Meakins-Christie Laboratories, Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, Quebec H2X 2P2, Canada.
J Immunol. 2012 Sep 15;189(6):2793-804. doi: 10.4049/jimmunol.1201194. Epub 2012 Aug 20.
Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2(-/-), or Tlr4(-/-) BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges. Nasal application of Protollin or Protollin admixed with BPEx was sufficient to inhibit allergic lower airway disease with minimal collateral lung inflammation. Inhibition was dependent on TLR4 and was associated with the induction of ICOS in cells of the nasal mucosa and on both CD4+Foxp3+ and CD4+Foxp3- T cells of the draining lymph nodes (LNs), as well as their recruitment to the lungs. Adoptive transfer of cervical LN CD4+ICOS+, but not CD4+ICOS-, cells inhibited BPEx-induced airway hyperresponsiveness and bronchoalveolar lavage eosinophilia. Thus, our data indicate that expansion of resident ICOS-expressing CD4+ T cells of the cervical LNs by nasal mucosal TLR4 stimulation may inhibit the development of allergic lower airway disease in mice.
通过先天免疫模式识别受体（如 TLRs）调节适应性免疫反应是疫苗开发的新兴策略。我们研究了鼻腔而非肺内应用 Protollin（一种由 TLR2 和 TLR4 配体组成的粘膜佐剂）是否足以引发对小鼠变应性下气道疾病的保护作用。野生型、Tlr2(-/-)或 Tlr4(-/-)BALB/c 小鼠致敏于桦树花粉过敏原提取物（BPEx），然后接受鼻腔内或肺内施用 Protollin 或 Protollin 与 BPEx 的混合物，随后连续每日接受 BPEx 挑战。鼻腔内应用 Protollin 或 Protollin 与 BPEx 的混合物足以抑制变应性下气道疾病，同时最小化肺旁炎症。抑制作用依赖于 TLR4，并与诱导鼻黏膜细胞中的 ICOS 以及引流淋巴结（LNs）中的 CD4+Foxp3+和 CD4+Foxp3-T 细胞有关，以及它们向肺部的募集。颈淋巴结 CD4+ICOS+而非 CD4+ICOS-细胞的过继转移可抑制 BPEx 诱导的气道高反应性和支气管肺泡灌洗嗜酸性粒细胞增多。因此，我们的数据表明，鼻腔粘膜 TLR4 刺激可扩增颈淋巴结中固有表达 ICOS 的 CD4+T 细胞，从而抑制小鼠变应性下气道疾病的发展。
