title: Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation.
abstract: Bacterial DNA contains immunostimulatory CpG motifs that trigger an innate immune response capable of promoting host survival following infectious challenge. Yet CpG-driven immune activation may also have deleterious consequences, ranging from autoimmune disease to death. We find that repetitive elements present at high frequency in mammalian telomeres, but rare in bacteria, down-regulate CpG-induced immune activation. Suppressive activity correlates with the ability of telomeric TTAGGG repeats to form G-tetrads. Colocalization of CpG DNA with Toll-like receptor 9 in endosomal vesicles is disrupted by these repetitive elements, although cellular binding and uptake remain unchanged. These findings are the first to establish that specific host-derived molecules can down-regulate the innate immune response elicited by a TLR ligand.
authors.affiliation: Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Gursel
authors.forename: Mayda
authors.initials: M
authors.lastname: Gursel
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018899:CpG Islands / Q000276:immunology; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000276:immunology; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004269:DNA, Bacterial; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D018664:Interleukin-12