Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1.

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  • Additional Information
    • Source:
      Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda, MD : American Association of Immunologists
      Original Publication: Baltimore : Williams & Wilkins, c1950-
    • Subject Terms:
      Dendritic Cells/*immunology ; Diabetes Mellitus, Type 1/*immunology ; Immunity, Innate/*immunology ; Interferon Type I/*immunology ; STAT1 Transcription Factor/*immunology ; Self Tolerance/*immunology; Active Transport, Cell Nucleus ; Animals ; Blotting, Western ; Cell Lineage ; Cell Nucleus/metabolism ; Dendritic Cells/cytology ; Dendritic Cells/metabolism ; Flow Cytometry ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Microscopy, Confocal ; Monocytes/cytology ; Monocytes/immunology ; Oligodeoxyribonucleotides/immunology ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction ; STAT1 Transcription Factor/metabolism ; Toll-Like Receptor 9/agonists
    • 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.
      Competing Interests: The authors have no financial conflicts of interest.
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    • Grant Information:
      Z01 DK069014-01 United States Intramural NIH HHS
    • Accession Number:
      0 (CpG ODN 2216)
      0 (Interferon Type I)
      0 (Oligodeoxyribonucleotides)
      0 (STAT1 Transcription Factor)
      0 (Stat1 protein, mouse)
      0 (Toll-Like Receptor 9)
    • Publication Date:
      Date Created: 20160131 Date Completed: 20160802 Latest Revision: 20191008
    • Publication Date:
      20221213
    • Accession Number:
      PMC5074843
    • Accession Number:
      10.4049/jimmunol.1501239
    • Accession Number:
      26826238