CpG-carrier size and density affects dendritic cell signaling, subset-tropism and systemic immune polarization
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Microbial pathogens range in size, shape, as well as biochemical and molecular properties. This has led to the evolution of a variety of pathogen recognition receptors (PRRs) in mammalian immune cells that are responsible for sensing pathogen-associated molecular patterns (PAMPs) and initiating specific types of immune responses. However, the breadth of the PRR responses, especially how dendritic cells sense pathogen physical properties in conjunction with specific molecular patterns and translate that into unique immune responses, remains unknown. Here, we have developed pathogen-like particles (PLPs) that mimic physical properties of large viruses or bacteria to demonstrate that CpG-mediated dendritic cell signaling can be precisely modulated by varying PLP parameters, specifically size and adjuvant density. We demonstrate controlled tunability of DC programming, allowing directed maturation of distinct T cell phenotypes, antibody class switching and in vivo immune-polarization. Furthermore, we show, for the first time, that the surface-density of CpG on PLPs can finely control DC signaling by regulating the kinetics of NFκB transcription and STAT3 phosphorylation. These findings suggest that DCs sense physical aspects of pathogen-like materials, broadening the tools that can be used to modulate immunity, better understand innate immune response mechanisms, and develop new and improved vaccines.