Leleux Jardin A, Pradhan Pallab, Roy Krishnendu
The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, The Parker H. Petit Institute for Bioengineering and Biosciences, Center for ImmunoEngineering at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Cell Rep. 2017 Jan 17;18(3):700-710. doi: 10.1016/j.celrep.2016.12.073.
It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP. These physical patterns control DC programming by regulating the kinetics and magnitude of MyD88-IRAK4 signaling, NF-κB-driven responses, and STAT3 phosphorylation, which, in turn, controls differential T cell responses and in vivo immune polarization, especially T helper 1 (Th1) versus T helper 2 (Th2) antibody responses. Our findings suggest that innate immune cells can sense and respond not only to molecular but also pathogen-associated physical patterns (PAPPs), broadening the tools for modulating immunity and helping to better understand innate response mechanisms to pathogens and develop improved vaccines.
目前尚不清楚哺乳动物病原体识别受体（PRR）是否以及如何对病原体相关分子危险信号的生物物理模式作出反应。我们使用模拟细菌或大型病毒物理特性的合成病原体样颗粒（PLP），发现小鼠树突状细胞（mDC）中CpG对Toll样受体9（TLR9）信号传导的质量和数量独特地依赖于生物物理属性；具体而言，是CpG的表面密度和呈递PLP的大小。这些物理模式通过调节MyD88-IRAK4信号传导、NF-κB驱动的反应以及STAT3磷酸化的动力学和幅度来控制树突状细胞编程，进而控制不同的T细胞反应和体内免疫极化，特别是辅助性T细胞1（Th1）与辅助性T细胞2（Th2）抗体反应。我们的研究结果表明，天然免疫细胞不仅可以感知并对分子作出反应，还能对病原体相关物理模式（PAPP）作出反应，拓宽了调节免疫的工具，并有助于更好地理解对病原体的天然反应机制以及开发改进的疫苗。
