Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses

• Published in: Cell reports (Cambridge) Vol. 18; no. 3; pp. 700 - 710
• Main Authors: Leleux, Jardin A., Pradhan, Pallab, Roy, Krishnendu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-01-2017; Elsevier
• Subjects: adjuvant delivery; adjuvant density; dendritic cells; immune modulation; immunotherapy; PAMP; PLGA; TLR9; vaccine delivery; vaccines; PAMP; vaccine delivery; dendritic cells; PLGA; vaccines; immunotherapy; adjuvant delivery; TLR9; adjuvant density; immune modulation
• ISSN: 2211-1247; 2211-1247
• 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.
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•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
Using synthetic pathogen-like particles (PLPs), Leleux et al. have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) is dependent on biophysical attributes, especially ligand density and size of the CpG-presenting carriers. These physical patterns control DC programming by regulating both stimulatory and anti-inflammatory signaling, which, in turn, controls in vivo immune polarization.