2. Innate immunity of the central nervous system: type I (IFN-α/β) and type III (IFN-λ) interferons
Type I interferons (IFNs) are a family of cytokines that play a critical role in the defense of the organism against viral infection. In addition, type I IFNs display cytostatic activities and modulate the acquired immune response. Thanks to these properties, type I IFNs are used in the treatment of viral hepatitis C, some cancers and multiple sclerosis.
In spite of their sequence divergences, all type I IFNs (IFN-α, IFN-β, IFN-κ, IFN-ε IFN-ω...) bind the same heterodimeric receptor made of the IFNAR-1 and IFNAR-2c subunits. IFN binding to the receptor activates the JAK1 and Tyk2 receptor-associated janus kinases which in turn phophorylate STAT signal transduction pathway (mostly STAT1 and STAT2). STAT1, STAT2 and IRF-9 associate to form the ISGF3 transcription factor responsible for the transcriptional upregulation of many genes called ISGs (Interferon Stimulated Genes). The proteins encoded by these genes (Mx, PKR, OAS...) are responsible for the antiviral, cytostatic and immunomodulatory activities of type I IFNs.
Type III IFNs (also called IL-28/IL-29 or IFNs-λ) were discovered recently. They bind to a receptor distinct from that of type I IFNs, made of the IL10Rβ and IL28Rα subunits. In spite of this different receptor usage, type III IFNs activate the same signal transduction pathway as type I IFNs and activate the same set of interferon stimulated genes.
Our group analyzes the reason for the multiplicity of type I IFN genes and for the apparent redundancy of the type I and type III IFN systems.
Production of IFNs in the CNS
We observed that the relative production of IFN-λ (over that of IFN-α/β) was low in the brain of mice infected with neurotropic viruses. Thus, the central nervous system appears to be both a poor producer of IFN-λ and a poor responder to this cytokine.
In contrast, IFN-α/β is readily produced in the central nervous system and we showed that neurons were able to contribute to the production of these IFNs in spite of the "immunoprivilege" of the central nervous system (Delhaye et al., PNAS, 2006).
We currently analyze the pathways involved in the production of IFNs in these particular cells.
Response to type I and type III IFNs:
Expression of IFNAR, the type I IFN receptor is widespread and most cells of the body can respond to these IFNs. In contrast, the response to IFN-λ exhibits striking tissue and cell specificity. In the organs analyzed, response to circulating IFN-λ was restricted to epithelial cells (Sommereyns et al., PloS Pathog. 2008). This suggests that IFN-λ evolved as a specific protection of epitheliums and mucosae. Our current research work addresses the relevance of such tissue and cell specificities of IFN responses.
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