Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses
Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses
复制标题
DOI：
10.1016/j.celrep.2016.12.073
复制
发表时间：
2017-01-17
期刊：
影响因子：
8.8
通讯作者：
Roy，Krishnendu
中科院分区：
文献类型：
--
作者：
Leleux，Jardin A.;Pradhan，Pallab;Roy，Krishnendu
目前尚不清楚哺乳动物病原体识别受体（PRRs）是否以及如何响应病原体相关分子危险信号的生物物理模式。利用模拟细菌或大型病毒物理特性的合成病原体样颗粒（PLPs），我们发现小鼠树突状细胞（mDCs）中CpG介导的toll样受体9 （TLR9）信号的质量和数量独特地依赖于生物物理特性；具体来说，CpG的表面密度和呈现的PLP的大小。这些物理模式通过调节MyD88-IRAK4信号传导、NF-κ b驱动反应和STAT3磷酸化的动力学和大小来控制DC编程，而STAT3磷酸化反过来又控制差异T细胞反应和体内免疫极化，特别是T辅助1 （Th1）对T辅助2 （Th2）抗体反应。我们的研究结果表明，先天免疫细胞不仅可以感知分子，还可以感知病原体相关的物理模式（PAPPs）并作出反应，从而拓宽了调节免疫的工具，有助于更好地了解病原体的先天反应机制并开发改进的疫苗。
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.