Infection and Immunity, University College London, London, United Kingdom.
PLoS One. 2011 Apr 1;6(4):e18346. doi: 10.1371/journal.pone.0018346.
The environmental mycobacterium, M. vaccae has been used in mouse models to support the contemporary hygiene hypothesis that non-pathogenic microorganisms reduce allergy associated T helper (Th)2 responses and inflammatory diseases by augmenting regulatory T cells. However, data for human models and possible mechanisms are limited. We tested the effect of innate immune interactions between human DC and M. vaccae on DC-dependent T cell responses. M. vaccae activation of DC via Toll like receptor (TLR)2 was compared to a specific TLR2 ligand (Pam(3)CSK4) and alternative stimulation with a TLR4 ligand (LPS). M. vaccae induced DC dependent inhibition of Th2 responses, in contrast to Pam(3)CSK4, which had the opposite effect and LPS, which had no polarizing effect. DC maturation, gene expression and cytokine production, in response to each stimulus did not correlate with the specific functional effects. Comparable DC transcriptional responses to M. vaccae and Pam(3)CSK4 suggested that TLR2 mediated transcriptional regulation was not sufficient for inhibition of Th2 responses. Transcription factor enrichment analysis and assessment of signaling events, implicated a role for selective early activation of the CREB pathway by M. vaccae. Further study of the CREB pathway may provide novel insight into the molecular mechanisms of DC-dependent T cell polarization.
环境分枝杆菌 M. vaccae 已被用于小鼠模型，以支持当代卫生假说，即非致病性微生物通过增强调节性 T 细胞来减少与过敏相关的辅助性 T 细胞（Th）2 反应和炎症性疾病。然而，人类模型的数据和可能的机制有限。我们测试了人类树突状细胞（DC）与 M. vaccae 之间先天免疫相互作用对 DC 依赖性 T 细胞反应的影响。通过 Toll 样受体（TLR）2 激活 DC 的 M. vaccae 与特定的 TLR2 配体（Pam（3）CSK4）和 TLR4 配体（LPS）的替代刺激进行了比较。与 Pam（3）CSK4 相反，M. vaccae 诱导了 DC 依赖性的 Th2 反应抑制，而 Pam（3）CSK4 则产生相反的效果，LPS 则没有极化作用。每种刺激物对 DC 成熟、基因表达和细胞因子产生的反应与特定的功能效果无关。M. vaccae 和 Pam（3）CSK4 对 DC 的相似转录反应表明，TLR2 介导的转录调控不足以抑制 Th2 反应。转录因子富集分析和信号事件评估表明，M. vaccae 对 CREB 途径的选择性早期激活可能起作用。对 CREB 途径的进一步研究可能为 DC 依赖性 T 细胞极化的分子机制提供新的见解。
