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. 2011 Dec;1(6):463-75.
doi: 10.1016/j.coviro.2011.10.026. Epub 2011 Nov 25.

Type I interferons: diversity of sources, production pathways and effects on immune responses

Melissa Swiecki  1 , Marco Colonna
Affiliations

Type I interferons: diversity of sources, production pathways and effects on immune responses

Melissa Swiecki et al. Curr Opin Virol. 2011 Dec.

Abstract

Type I interferons (IFN-I) were first described over 50 years ago as factors produced by cells that interfere with virus replication and promote an antiviral state. Innate and adaptive immune responses to viruses are also greatly influenced by IFN-I. In this article we discuss the diversity of cellular sources of IFN-I and the pathways leading to IFN-I production during viral infections. Finally, we discuss the effects of IFN-I on cells of the immune system with emphasis on dendritic cells.

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Figures

Figure 1
Figure 1. Cellular sources of IFN-I during virus infections
The cells involved in the production of IFN-I depend on the route of infection and tissue tropism of the virus. During skin and mucosal infections, epithelial cells, fibroblasts, tissue resident macrophages and DCs secrete IFN-I and restrict viral replication. In infected organs, IFN-I is produced by parenchymal cells, fibroblasts, tissue resident macrophages and DCs. In draining lymph nodes, subcapsular sinus macrophages have a major role in the secretion of IFN-I and restriction of viral spread. During systemic virus infections, marginal zone macrophages, pDCs, monocytes and non-hematopoietic stromal cells contribute to IFN-I production and viral containment.
Figure 2
Figure 2. Molecular sensors involved in virus recognition and IFN-I production
Toll-like receptors (TLR), RIG-I-like receptors (RIG-I, MDA5, LGP2) and newly identified cytoplasmic nucleic acid sensors detect microbial products and initiate IFN-I secretion. TLR2 is expressed by cDCs, monocytes and macrophages and senses viral ligands such as hemagglutinin. TLR7/8 detects ssRNA and are expressed by pDCs, cDCs, monocytes, macrophages and B cells. TLR9 is expressed by pDCs, cDCs (in mouse, not human), macrophages and B cells and recognizes dsDNA. TLR3 detects dsRNA and is expressed mainly in cDCs, macrophages, B cells and stromal cells. RLRs are induced by IFN-I and sense distinct forms of RNA. LGP2 lacks signaling domains and may regulate MDA5 and RIG-I. Unlike TLRs, RLRs have a more broad cellular and tissue distribution. Cytoplasmic nucleic acid sensors such as DDX1, DDX21, DDX36, DDX9, DDX36 and DDX41 have been recently identified and appear to be more restricted in their expression patterns (i.e. cDC or pDC).
Figure 3
Figure 3. Effects of IFN-I on cells during virus infections
IFN-I promote the death of virus-infected cells through the induction of pro-apoptotic molecules involved in the extrinsic (TRAIL/DR4/DR5 or Fas/FasL) and intrinsic (i.e. p53, Bim, Bid, Bax, Noxa, Puma) apoptosis pathways. In addition, IFN-I act on uninfected cells by inducing hundreds of interferon-stimulated genes (ISGs) that restrict viral replication and confer an antiviral state. The maturation, expansion and effector functions of NK cells, T and B cells, DCs and macrophages are also profoundly influenced by IFN-I. mDC, mature DC.
Figure 4
Figure 4. Effects of IFN-I on dendritic cell subsets
IFN-I promote the migration, maturation and antigen (Ag) presenting capabilities of DCs. IFN-I also induces the differentiation of monocytes into a specialized subset of DC called interferon-induced DC (IFN-DC). Recent evidence suggests that IFN-I regulates DC turnover. Both splenic cDCs and pDCs upregulate caspases and molecules involved in the intrinsic apoptosis pathway following exposure to IFN-I. Furthermore, dormant hematopoietic stem cells (HSC) are activated by IFN-I to proliferate and differentiate which may replace activated or dying DCs during antiviral responses. The regulated turnover of cDCs and pDCs during IFN-I-mediated responses may be a mechanism to prevent excessive immune stimulation and immunopathology. iDC, immature DC; mDC, mature DC.
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