Cell Reports
Volume 18, Issue 3, 17 January 2017, Pages 700-710
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Article
Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses

https://doi.org/10.1016/j.celrep.2016.12.073Get rights and content
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Highlights

  • Biophysical attributes of particles can modulate TLR9 signaling in dendritic cells

  • The density of CpG on particle carriers affects signaling along the TLR9-MyD88-NF-κB axis

  • Particle parameters affect STAT3 phosphorylation, regulating dendritic cell signaling

  • Physical pattern-driven dendritic cell programming skews in vivo immune polarization

Summary

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.

Keywords

TLR9
dendritic cells
PAMP
adjuvant density
vaccines
PLGA
immunotherapy
immune modulation
vaccine delivery
adjuvant delivery

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