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

• Main Authors: Jardin A. Leleux, Pallab Pradhan, Krishnendu Roy
• Format: Article
• Language: English
• Published: Elsevier 2017-01-01
• Series: Cell Reports
• Subjects: TLR9; dendritic cells; PAMP; adjuvant density; vaccines; PLGA; immunotherapy; immune modulation; vaccine delivery; adjuvant delivery
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124716317958

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.