Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells
Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells
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DOI：
10.1016/j.jaci.2007.09.045
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发表时间：
2008-02-01
影响因子：
14.2
通讯作者：
Novak, Natalija
中科院分区：
文献类型：
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作者：
Allam, Jean-Pierre;Peng, Wen-Ming;Novak, Natalija
背景：尽管细菌定植率高，但口腔粘膜急性感染罕见，提示耐受性占优势。目的：Toll样受体4（Toll-like receptor 4，TLR 4）激动剂monosphoryl lipid A已被成功地用作皮下免疫治疗的佐剂，提示增强过敏原特异性耐受。最近舌下免疫疗法（SLIT）已被证明是皮下免疫疗法的有效替代方案。我们观察到CD 14在人口腔Langerhans细胞（oLC）上的表达，其代表SLIT的主要靶点。方法：用胰蛋白酶消化人口腔粘膜，获得细胞悬液，用流式细胞仪、RT-PCR、流式细胞仪微球阵列、ELISA和混合淋巴细胞反应等方法进行分析。我们可以证明oLCs表达TLR 4，与单球酰脂质A连接后，共抑制分子B7-H1和B7-H3的表达上调，同时共刺激分子CD 86的表面表达降低。此外，TLR 4在oLC上的连接增加了它们的抗炎细胞因子IL-10的释放，并降低了它们对T细胞的刺激能力。此外，TLR 4-ligation的oLCs诱导IL-10，TGF-β 1，叉头盒蛋白3，IFN-γ，和IL-2production.Conclusion：鉴于这些数据，TLR 4-ligation的oLCs可能不仅在病原体识别有效的免疫中发挥作用，但也有助于在口腔中占主导地位的致耐受性状态。
Background: Despite high bacterial colonization, acute infections are rare in the oral mucosa, implicating tolerogenic predominance. Bacterial antigens like LPSs are recognized by innate immunity receptors such as Toll-like receptor 4 (TLR4), associated with LPS receptor (CD14).Objectives: Toll-like receptor 4 agonist monosphoryl lipid A has been successfully used as adjuvant in subcutaneous immunotherapy, suggesting reinforcement of allergen-specific tolerance. Recently sublingual immunotherapy (SLIT) has been shown to be an effective alternative to subcutaneous immunotherapy. We observed CD14 expression on human oral Langerhans cells (oLCs), representing a major target of SLIT. However, not much is known about TLR4 expression and its effect on oLCs.Methods: Cell suspensions were obtained by trypsinization of human oral mucosa and analyzed by flow cytometry, RT-PCR, cytometric bead arrays, ELISA, and mixed lymphocyte reactions.Results: We could show that oLCs express TLR4, and its ligation by monosphoryl lipid A upregulated expression of coinhibitory molecules B7-H1 and B7-H3 while surface expression of costimulatory molecule CD86 was concomitantly decreased. Furthermore, TLR4 ligation on oLCs increased their release of the anti-inflammatory cytokine IL-10 and decreased their stimulatory capacity toward T cells. Moreover, TLR4-ligation on oLCs induced IL-10, TGF-beta 1, Forkhead box protein 3, IFN-gamma, and IL-2 production in T cells.Conclusion: In view of these data, TLR4-ligation on oLCs might not only play a role in pathogen recognition for efficient immunity but also contribute to the tolerogenic state predominating in the oral cavity.