Abstract
The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl(-/-) dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl(-/-) mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl(-/-) mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity.
Highlights
AXL is a member of the TAM (TYRO3, AXL, and MERTK) subfamily of receptor tyrosine kinase (RTK) that potently inhibits the production of type I IFNs (Bhattacharyya et al, 2013; Rothlin et al, 2015; Rothlin et al, 2007; Zagorska et al, 2014)
The increased susceptibility of Axl-/- mice to influenza A virus (IAV) infection correlated with higher viral titers in the bronchoalveolar lavage (BAL) fluid than in WT mice 7 and 9 days postinfection (Figure 1B), corresponding to when the CD8+ T cell response is critical in viral clearance
In vitro experiments have led to the speculation that AXL promotes the infection of several enveloped viruses including vaccinia (Morizono et al, 2011), Lassa (Shimojima et al, 2012), dengue (Meertens et al, 2012), and West Nile virus (WNV) (Bhattacharyya et al, 2013)
Summary
AXL is a member of the TAM (TYRO3, AXL, and MERTK) subfamily of RTK that potently inhibits the production of type I IFNs (Bhattacharyya et al, 2013; Rothlin et al, 2015; Rothlin et al, 2007; Zagorska et al, 2014). Recent studies using an array of enveloped viruses have identified AXL as an enhancer of infection in vitro, including in DCs (Bhattacharyya et al, 2013; Meertens et al, 2012; Morizono et al, 2011; Shimojima et al, 2007; 2012). Enveloped viruses exploit apoptotic mimicry by exposing phosphatidylserine on their lipid envelopes. Activation of AXL through viral apoptotic mimicry leads to the induction of the Socs genes and the suppression of type I IFN production and signaling (Bhattacharyya et al, 2013).
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