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

It is currently unknown whether and how mammalian pathogen-recognition receptors (PRR) 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 (mDC) is 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 kinetics and magnitude of MyD88-IRAK4 signaling, NFκB-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, helping to better understand innate response mechanisms to pathogens and develop new and improved vaccines.