title: Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses.
abstract: 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.
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, The Parker H. Petit Institute for Bioengineering and Biosciences, Center for ImmunoEngineering at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: jleleux3@gatech.edu.
authors.forename: Jardin A
authors.initials: JA
authors.lastname: Leleux
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, The Parker H. Petit Institute for Bioengineering and Biosciences, Center for ImmunoEngineering at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: ppiitb@gmail.com.
authors.forename: Pallab
authors.initials: P
authors.lastname: Pradhan
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, The Parker H. Petit Institute for Bioengineering and Biosciences, Center for ImmunoEngineering at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: krish.roy@gatech.edu.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Roy
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051217:Toll-Like Receptor 9; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse
keywords: PAMP; PLGA; TLR9; adjuvant delivery; adjuvant density; dendritic cells; immune modulation; immunotherapy; vaccine delivery; vaccines