title: Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1.
abstract: Innate immune signals help break self-tolerance to initiate autoimmune diseases such as type 1 diabetes, but innate contributions to subsequent regulation of disease progression are less clear. Most studies have measured in vitro innate responses of GM-CSF dendritic cells (DCs) that are functionally distinct from conventional DCs (cDCs) and do not reflect in vivo DC subsets. To determine whether autoimmune NOD mice have alterations in type 1 IFN innate responsiveness, we compared cDCs from prediabetic NOD and control C57BL/6 (B6) mice stimulated in vivo with the TLR9 ligand CpG, a strong type 1 IFN inducer. In response to CpG, NOD mice produce more type 1 IFN and express higher levels of CD40, and NOD monocyte DCs make more TNF. However, the overall CpG-induced transcriptional response is muted in NOD cDCs. Of relevance the costimulatory proteins CD80/CD86, signals needed for regulatory T cell homeostasis, are upregulated less on NOD cDCs. Interestingly, NOD Rag1(-/-) mice also display a defect in CpG-induced CD86 upregulation compared with B6 Rag1(-/-), indicating this particular innate alteration precedes adaptive autoimmunity. The impaired response in NOD DCs is likely downstream of the IFN-α/β receptor because DCs from NOD and B6 mice show similar CpG-induced CD86 levels when anti-IFN-α/β receptor Ab is added. IFN-α-induced nuclear localization of activated STAT1 is markedly reduced in NOD CD11c(+) cells, consistent with lower type 1 IFN responsiveness. In conclusion, NOD DCs display altered innate responses characterized by enhanced type 1 IFN and activation of monocyte-derived DCs but diminished cDC type 1 IFN response.
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: M Jubayer
authors.identifier: http://orcid.org/0000-0002-4496-8385
authors.initials: MJ
authors.lastname: Rahman
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Rahir
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dong
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Yongge
authors.identifier: http://orcid.org/0000-0003-4466-2391
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Kameron B
authors.identifier: http://orcid.org/0000-0002-0270-3688
authors.initials: KB
authors.lastname: Rodrigues
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Chie
authors.identifier: http://orcid.org/0000-0002-5501-8553
authors.initials: C
authors.lastname: Hotta-Iwamura
authors.affiliation: Bioinformatics and Systems Biology Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ye
authors.identifier: http://orcid.org/0000-0001-8785-7653
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Alan
authors.initials: A
authors.lastname: Guerrero
authors.affiliation: Immune Tolerance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and tarbellk@niddk.nih.gov.
authors.forename: Kristin V
authors.identifier: http://orcid.org/0000-0003-3738-379X
authors.initials: KV
authors.lastname: Tarbell
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists
chemical_list: C526902:CpG ODN 2216; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051217:Toll-Like Receptor 9
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