Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bioinformatics Group, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Syst. 2017 Jul 26;5(1):25-37.e3. doi: 10.1016/j.cels.2017.06.014.
A typical pathogen presents a combination of Toll-like receptor (TLR) ligands during infection. Although individual TLR pathways have been well characterized, the nature of this "combinatorial code" in pathogen sensing remains unclear. Here, we conducted a comprehensive transcriptomic analysis of primary macrophages stimulated with all possible pairwise combinations of four different TLR ligands to understand the requirements, kinetics, and outcome of combined pathway engagement. We find that signal integration between TLR pathways leads to non-additive responses for a subset of immune mediators with sustained expression (>6 hr) properties and T cell polarizing function. To identify the underlying regulators, we conducted a focused RNAi screen and identified four genes-Helz2, Phf11d, Sertad3, and Zscan12-which preferentially affect the late phase response of TLR-induced immune effector expression. This study reveals key molecular details of how contemporaneous signaling through multiple TLRs, as would often be the case with pathogen infection, produce biological outcomes distinct from the single ligands typically used to characterize TLR pathways.
在感染过程中，典型的病原体呈现出 Toll 样受体 (TLR) 配体的组合。尽管单个 TLR 途径已经得到很好的描述，但病原体感应中这种“组合密码”的性质仍不清楚。在这里，我们对用四种不同 TLR 配体的所有可能的两两组合刺激的原代巨噬细胞进行了全面的转录组分析，以了解联合途径参与的要求、动力学和结果。我们发现，TLR 途径之间的信号整合导致一部分免疫介质的反应不是加性的，这些免疫介质具有持续表达（>6 小时）的特性和 T 细胞极化功能。为了鉴定潜在的调节剂，我们进行了靶向 RNAi 筛选，鉴定了四个基因——Helz2、Phf11d、Sertad3 和 Zscan12——它们优先影响 TLR 诱导的免疫效应物表达的晚期反应。这项研究揭示了关键的分子细节，即多个 TLR 的同时信号传递（如病原体感染通常发生的情况）如何产生与通常用于表征 TLR 途径的单一配体不同的生物学结果。
