Lyme Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD.
J Immunol. 2023 Aug 15;211(4):612-625. doi: 10.4049/jimmunol.2300235.
Dendritic cells bridge the innate and adaptive immune responses by serving as sensors of infection and as the primary APCs responsible for the initiation of the T cell response against invading pathogens. The naive T cell activation requires the following three key signals to be delivered from dendritic cells: engagement of the TCR by peptide Ags bound to MHC molecules (signal 1), engagement of costimulatory molecules on both cell types (signal 2), and expression of polarizing cytokines (signal 3). Initial interactions between Borrelia burgdorferi, the causative agent of Lyme disease, and dendritic cells remain largely unexplored. To address this gap in knowledge, we cultured live B. burgdorferi with monocyte-derived dendritic cells (mo-DCs) from healthy donors to examine the bacterial immunopeptidome associated with HLA-DR. In parallel, we examined changes in the expression of key costimulatory and regulatory molecules as well as profiled the cytokines released by dendritic cells when exposed to live spirochetes. RNA-sequencing studies on B. burgdorferi-pulsed dendritic cells show a unique gene expression signature associated with B. burgdorferi stimulation that differs from stimulation with lipoteichoic acid, a TLR2 agonist. These studies revealed that exposure of mo-DCs to live B. burgdorferi drives the expression of both pro- and anti-inflammatory cytokines as well as immunoregulatory molecules (e.g., PD-L1, IDO1, Tim3). Collectively, these studies indicate that the interaction of live B. burgdorferi with mo-DCs promotes a unique mature DC phenotype that likely impacts the nature of the adaptive T cell response generated in human Lyme disease.
树突状细胞通过作为感染的传感器和负责启动针对入侵病原体的 T 细胞反应的主要 APC，连接先天和适应性免疫反应。幼稚 T 细胞的激活需要来自树突状细胞的以下三个关键信号的传递：TCR 与 MHC 分子结合的肽 Ag 的结合（信号 1），两种细胞类型上的共刺激分子的结合（信号 2），以及极化细胞因子的表达（信号 3）。伯氏疏螺旋体（导致莱姆病的病原体）与树突状细胞之间的初始相互作用在很大程度上仍未得到探索。为了解决这一知识空白，我们培养了来自健康供体的单核细胞衍生的树突状细胞（mo-DC）中的活伯氏疏螺旋体，以研究与 HLA-DR 相关的细菌免疫肽组。同时，我们还研究了关键共刺激和调节分子表达的变化，并分析了暴露于活旋体时树突状细胞释放的细胞因子。对 B. burgdorferi 脉冲树突状细胞的 RNA 测序研究显示，与刺激 TLR2 激动剂脂磷壁酸不同，与 B. burgdorferi 刺激相关的独特基因表达特征。这些研究表明，mo-DC 暴露于活的 B. burgdorferi 会驱动促炎和抗炎细胞因子以及免疫调节分子（例如 PD-L1、IDO1、Tim3）的表达。总之，这些研究表明，活的 B. burgdorferi 与 mo-DC 的相互作用促进了独特的成熟 DC 表型，这可能影响人类莱姆病中产生的适应性 T 细胞反应的性质。
