Abstract
During virus infection and autoimmune disease, inflammatory dendritic cells (iDCs) differentiate from blood monocytes and infiltrate infected tissue. Following acute infection with hepatotropic viruses, iDCs are essential for re-stimulating virus-specific CD8+ T cells and therefore contribute to virus control. Here we used the lymphocytic choriomeningitis virus (LCMV) model system to identify novel signals, which influence the recruitment and activation of iDCs in the liver. We observed that intrinsic expression of Toso (Faim3, FcμR) influenced the differentiation and activation of iDCs in vivo and DCs in vitro. Lack of iDCs in Toso-deficient (Toso–/–) mice reduced CD8+ T-cell function in the liver and resulted in virus persistence. Furthermore, Toso–/– DCs failed to induce autoimmune diabetes in the rat insulin promoter-glycoprotein (RIP-GP) autoimmune diabetes model. In conclusion, we found that Toso has an essential role in the differentiation and maturation of iDCs, a process that is required for the control of persistence-prone virus infection.
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Abbreviations
- ALT:
-
Alanine-amino transferase
- β-ME:
-
Beta-mercaptoethanol
- BMDC:
-
Bone marrow-derived dendritic cell
- FACS:
-
Fluorescence-activated cell sorting
- GM-CSF:
-
Granulocyte macrophage colony-stimulating factor
- GP:
-
Glycoprotein
- IL-6:
-
Interleukin-6
- iDC:
-
inflammatory dendritic cell
- iNOS:
-
inducible nitric oxide synthase
- IFN-γ:
-
Interferon-gamma
- IL7Rα:
-
Interleukin-7 receptor alpha chain
- iMATE:
-
Intrahepatic myeloid cell aggregate
- LPS:
-
Lipopolysaccharide
- LCMV:
-
Lymphocytic choriomeningitis virus
- LCMV-GP:
-
LCMV glycoprotein
- LCMV-GP33:
-
LCMV glycoprotein 33–41
- MFI:
-
Mean fluorescence intensity
- MHC:
-
Major histocompatibility complex
- NF-κB:
-
Nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells
- PD-1:
-
Programmed cell death-1
- RIP:
-
Rat insulin promoter
- PFU:
-
Plaque-forming unit
- TLR:
-
Toll-like receptor
- TNF-α:
-
Tumor necrosis factor alpha
- Tip-DCs:
-
TNF-α and iNOS producing DCs
- WT:
-
Wild type
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Acknowledgements
This study was supported by the Alexander von Humboldt Foundation (SKA2008 to KSL and SKA2010 to PAL). Furthermore, this study was supported by the German Research Council (TRR60, CRC974, LA2558-3-5/1, LA1419/5-1). This work was also supported by CIHR. DB was supported by a postdoctoral fellowship from the German Research Foundation (DFG).
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Lang, P., Meryk, A., Pandyra, A. et al. Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection. Cell Death Differ 22, 164–173 (2015). https://doi.org/10.1038/cdd.2014.138
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DOI: https://doi.org/10.1038/cdd.2014.138
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