AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity

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.The immune system must be ever vigilant to ward off infections. Immune cells called T-cells can identify and eliminate microbes, but if they are too aggressive, they can damage the body. To prevent this, the body has systems that control immune responses. For example, another type of immune cell called a dendritic cell produces proteins known as type 1 interferons, which help to fight viral infections while limiting other immune responses.An enzyme called AXL blocks the production of type 1 interferons. Many scientists believe that this activity reduces the ability of individual cells in the body to defend themselves against attacking viruses. In fact, experiments with cells grown in the laboratory have shown that some viruses activate the AXL enzyme to help them infect. Similar studies have also shown that inhibiting AXL and related enzymes can make cells more able to fight off certain types of viral infection. These and other studies suggested that some drugs that block AXL might be useful treatments for viral infections, however it was not clear if this was the case for all viruses.Now, Schmid et al. show that the loss of AXL actually makes mice more prone to infections by the influenza virus and West Nile Virus. In the experiments, mice genetically engineered to lack AXL were more likely than normal mice to become ill after exposure to one of the viruses. Furthermore, fewer T cells matured to the stage where they could attack the virus in these mice.Next, Schmid et al. show that blocking the production of type 1 interferons in the mice that lack AXL restores their ability to fight off these viral infections. This is because type 1 interferons limit the production of a protein that helps the dendritic cells to mature. Therefore, Schmid et al.’s findings show that AXL is vital for mice to fight off viral infections because it helps to balance the antiviral and immune suppressing activities of type 1 interferons. The findings also suggest that using drugs that block AXL to treat infections with certain viruses, including influenza and West Nile Virus, might do more harm than good.