After a long week of high school, I came home ready to unwind. I ate a quick meal, brushed my teeth and went to bed early that Friday evening. I woke up thinking I had slept peacefully through the night, but it turns out I had slept through the entire weekend. My parents, relieved that I was finally awake, noticed my sickly appearance accompanied with a high fever and immediately drove me to the urgent care where I was diagnosed with swine flu.

The 2009 swine flu pandemic had hit me and thousands of others hard. While researchers have been studying the various forms of the flu, or influenza, for decades, many mysteries about the virus and our body’s immune response to this disease still remain.

When the influenza virus infects us, our body mounts an immune response to fight off this invader. Among the many defenses in our body’s repertoire, there are a group of messenger proteins known as cytokines. These immune proteins signal that an invader has entered the system and help orchestrate the correct immune response. Of these many immune proteins, interferon-lambda (IFN-λ) is one of the most critical for our bodies to mount an appropriate antiviral response. IFN-λ has a well-known signalling function in the innate or early immune response but whether it’s involved in establishing long-term antiviral responses is not understood. That’s where Ye et al. came in.

In a study published recently in Nature Immunology, the researchers infected mice defective for the IFN-λ receptor with a strain of influenza virus that induces a more potent immune response than normal. Mice missing the receptor, and therefore lacking any immune response that might be mediated by IFN-λ, had decreased adaptive immune function as measured by common markers like antibody production and mature T or immune cell presence.

To investigate whether this immune response was generalized or location-specific, the authors administered two commercially-available influenza vaccines with or without the addition of IFN-λ via three different routes: intranasally to target the lungs and respiratory tract, in the mice’s tails to get the vaccine directly into the blood and throughout the body, and subcutaneously to get a slower, more localized immune response. They observed that IFN-λ increased overall immune response only in mice that received the vaccine intranasally, suggesting the effect of IFN-λ on the long-term immune response might be exclusive to the upper respiratory tract.

The authors then looked for potential downstream signaling targets known to be abundant and exclusive to the respiratory tract. They became interested in thymic stromal lymphopoietin, or TSLP for short. This cytokine has a well-established role in mucosal immunity, the immune response unique to mucus-producing tissues like the lungs and gut. When tested, TSLP also produced adaptive immune responses similar to the one the authors had seen from IFN-λ, suggesting the two might be working together.

To look at this potential collaboration, the authors added TSLP to the intranasally immunized mice and also knocked out or blocked this cytokine. When TSLP was absent, IFN-λ didn’t have as strong of an immune-inducing effect. Subsequently, the researchers saw similar immune responses in the mice when they added TSLP during immunization when compared to IFN-λ. These data suggest that IFN-λ works with and relies on respiratory tract-specific TSLP to help stimulate a long term immune response.

Digging even deeper, the authors wanted to see how this dynamic duo could influence long term immunity to influenza virus. Using a similar setup, Ye et al. intranasally immunized either normal, healthy mice or mice lacking TSLP, with or without the presence of IFN-λ. They then measured levels of different immune cells, specifically immune cells that are important for the development of long term immunity. IFN-λ promoted the development of an adaptive immune response to influenza that was TSLP-dependent. Overall, these data suggest a novel role for IFN-λ in the development of immune memory and long term immunity.

Finally, the authors questioned if IFN-λ could be used as an adjuvant, an additional component to vaccines that helps strengthen the body’s immune response. When added to a commercially available flu vaccine, mice maintained a relatively normal weight and survived an influenza infection. Additionally, total numbers of virus went down in the immunized and adjuvanted mice, suggesting a decreased potential for transmission as well.

Overall, Ye et al. have shown a novel and exciting role for IFN-λ in helping to establish long-term immunity against influenza virus. However, let’s not forget that this cytokine relies on its teammate, TSLP, to fully elicit an immune response. The identification of this immune relationship potentially gives us new therapeutic targets and could help to improve future flu vaccine development. Additionally, this opens the door for researchers to explore IFN-λ and TSLP’s roles in adaptive immunity for other respiratory specific viruses—bringing us another step closer to better, more effective vaccines and less weekends (unknowingly) slept through.

Reference:
Ye, L., Schnepf, D., Becker, J. et al. Interferon-λ enhances adaptive mucosal immunity by boosting release of thymic stromal lymphopoietin. Nat Immunol 20, 593–601 (2019) doi:10.1038/s41590-019-0345-x

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