title: IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences.
abstract: Immunostimulatory sequences (ISS) are short oligonucleotides containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides that stimulate innate immune responses through Toll-like receptor-9 on B cells and plasmacytoid dendritic cell (PDC) precursors. The anti-inflammatory cytokine interleukin (IL)-10 is predicted to be a potent inhibitor of many of the activities described for ISS, and this may impact the use of ISS in disease states characterized by elevated IL-10. As the activities of ISS on PDCs are central to many clinical applications of ISS, we have studied the effects of IL-10 on PDC stimulation by 3 distinct classes of ISS. IL-10 inhibited cytokine production and survival of ISS-activated PDCs; however, IL-12 induction was much more sensitive to inhibition than interferon (IFN)-alpha induction. Within the PDC population are cells that respond to ISS by producing either IL-12 or IFN-alpha but not both cytokines. IL-12-producing PDCs require costimulation through CD40 and appear more mature than IFN-alpha-producing PDCs. The 3 distinct classes of ISS differed with respect to induction of PDC maturation and T-cell priming capacity. IL-10 regulated PDC activation but did not inhibit the subsequent T-cell-priming ability of PDCs already activated by ISS.
authors.affiliation: Dynavax Technologies, 717 Potter St, Ste 100, Berkeley, CA 94710, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Duramad
authors.forename: Karen L
authors.initials: KL
authors.lastname: Fearon
authors.forename: Jean H
authors.initials: JH
authors.lastname: Chan
authors.forename: Holger
authors.initials: H
authors.lastname: Kanzler
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
mesh_terms: D000276:Adjuvants, Immunologic / Q000145:classification / Q000494:pharmacology*; D017951:Antigen Presentation; D019013:CD40 Antigens / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000494:pharmacology* / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D007377:Interleukin-3 / Q000494:pharmacology; D008213:Lymphocyte Activation; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D016898:Interferon-alpha; D007377:Interleukin-3; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma