Despite Increased Type 1 IFN, Autoimmune Nonobese Diabetic Mice Display Impaired Dendritic Cell Response to CpG and Decreased Nuclear Localization of IFN-Activated STAT1
| Autor: | Yongge Zhao, Chie Hotta-Iwamura, M. Jubayer Rahman, Alan D. Guerrero, Matthew B. Dong, Kameron B. Rodrigues, Yi Chen, Kristin V. Tarbell, Gwendoline Rahir |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Regulatory T cell Blotting Western Immunology Active Transport Cell Nucleus chemical and pharmacologic phenomena Nod Biology Real-Time Polymerase Chain Reaction Article Monocytes Mice 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD medicine Animals Immunology and Allergy Cell Lineage Oligonucleotide Array Sequence Analysis NOD mice Cell Nucleus CD86 Microscopy Confocal Innate immune system Monocyte TLR9 hemic and immune systems Dendritic Cells Dendritic cell Flow Cytometry Immunity Innate Mice Inbred C57BL Diabetes Mellitus Type 1 STAT1 Transcription Factor Self Tolerance 030104 developmental biology medicine.anatomical_structure Oligodeoxyribonucleotides Toll-Like Receptor 9 Interferon Type I 030215 immunology |
| Zdroj: | The Journal of Immunology. 196:2031-2040 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1501239 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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