Journal of Interferon and Cytokine Research: You recently published a landmark study describing a role for interferon (IFN)-λ in immunity against influenza virus infection. What was the main focus of the study, and what were your major findings in terms of IFN-λ biology?
Emily Hemann: I had always been interested in how innate immune signaling molecules and pathways such as IFN-λ have contributed to adaptive immune responses. When I started this project, it was known that IFN-λ played a role in regulating antiviral responses against influenza virus infection, but the role that IFN-λ could be playing in adaptive immunity against influenza virus infection had really not been explored.
To determine this, we infected IFN-λ receptor knockout mice with influenza virus and found a significant reduction in their influenza virus-specific CD8 T cell responses. We know that cellular CD8 T cell immunity is really important for clearing influenza virus infection and also providing memory protection against subsequent infection when you have things such as genetic shifts in the virus or antibodies that are subverted due to virus mutation. We modeled this in our mouse model of infection and found that under conditions without antibody-mediated protection, in the absence of IFN-λ signaling, these mice were not able to respond as well to a subsequent influenza virus challenge. Basically, what we had shown was that IFN-λ signaling is critical to mediating protection against influenza virus infection in a situation wherein you are exposed to a new virus and do not yet have protective antibody responses.
We started to look into the mechanisms of how IFN-λ was mediating protection against influenza virus infection. We assessed the CD8 T cell response to infection, and we found out that the susceptibility of mice lacking signaling to IFN-λ was not due to a CD8 T cell intrinsic defect. Instead, there was a defect in the ability of dendritic cells to function in the absence of IFN-λ signaling. To investigate this defect, we performed transcriptomic analyses and found a number of genes that were being differentially regulated in the absence of IFN-λ signaling during influenza virus infection. We honed in on an immunoregulatory gene network that seemed to be activated specifically in the absence of IFN-λ signaling. In the published study, we show that in the absence of IFN-λ signaling, these dendritic cells instead of activating T cells were now upregulating interleukin (IL)-10, an immunosuppressive cytokine, and that IL-10 levels associated with the reduction in the CD8 T cell response during influenza infection. This is where the first story left off.
We are now following up on a number of directions, to figure out how IFN-λ is regulating dendritic cell responses more specifically, and also how IFN-λ impacts the seeding of these memory responses.
JICR: It seems that IFN-λ was important for immune programming. Are these actions working at the level of in-between innate and adaptive immunity, like at the interface of innate and adaptive immune responses?
Emily Hemann: What was really interesting and what we did not expect was when we saw this outcome in a lack of protection, it is not happening just in an isolated manner within the adaptive population. The defect we were observing was not intrinsic to those CD8 T cells, it was really a defect we were observing in the dendritic cell response that was leading to a defect in the ability of these CD8 T cells to then respond. This was truly a role for IFN-λ at that innate–adaptive immune interface. Not just being relegated to one compartment or the other, but manifesting in the innate immune cells and having an outcome in the adaptive immune cells. IFN-λ really works in concert at the innate–adaptive interface.
JICR: How can we harness IFN-λ for therapeutic applications to enhance vaccine immunity?
Emily Hemann: Pegylated IFN-λ has been developed and has been tested in a murine model of attenuated influenza virus infection. It has been shown to enhance antibody responses in a previous study, from another group. Based on this previously published study and the role that we have identified for IFN-λ in regulating dendritic cell responses that are important for T cell priming, we think that IFN-λ may be able to be administered to augment CD8 T cell immunity in the context of multiple kinds of influenza vaccines.
JICR: Are there any toxic actions associated with IFN-λ and the response that it generates in the body?
Emily Hemann: Generally speaking, one of the potential benefits of IFN-λ relative to type 1 IFN, which are commonly compared because they have similar downstream signaling pathways, is that IFN-λ has been described as being much less inflammatory. This has been well established in cell lines and murine models. There have also been recent phase 2 clinical trials where pegylated IFN-λ has been administered in the context of SARS-CoV-2 infection, as an antiviral and not as a vaccine, and in this antiviral context it did not seem to cause any adverse reactions. It seems as though the clinical trial data support what has been observed in our experimental models, and those of others, that IFN-λ is less inflammatory than type 1 IFN and should not have the same kinds of adverse or toxic side effects.
JICR: You just started your own laboratory at The Ohio State University. Has it been difficult starting a laboratory during the SARS-CoV-2/COVID-19 pandemic?
Emily Hemann: Starting a laboratory at any time is difficult. There have been significant delays on pretty much all fronts due to the pandemic. I do not have a before or after comparison, but I officially started in my position here in August of 2020, when most of the administrative and support staff members were already working remotely. That definitely slowed down things like getting protocols approved, having inspections, and all of the things you need to do to start a laboratory. That being said, everyone has been very helpful and understanding, especially the other faculty in the department. In addition, supply chain and shortage issues have made it difficult to order everything from −80°C freezers to pipette tips, but those are more global issues impacting every laboratory. However, we have managed to get the laboratory set up and are again doing experiments. Hopefully a lot of the shortages and ordering issues related to the pandemic will be subsiding going forward.
JICR: Besides the pandemic, what hurdles have you faced in starting your new laboratory?
Emily Hemann: Some of the more typical challenges of starting a new laboratory have been associated with establishing our mouse colonies. There currently are not many in vitro models we use so we rely a lot on mouse models of infection to look at these complex immune cell interactions. The months it has taken to get the mouse colonies up and running has been an anxious waiting game. Recruiting individuals to the laboratory has also been a challenge, especially in the middle of a pandemic, but we now have a graduate student and a research associate who have joined the group. We are now actively looking to expand the group now that we have had restrictions loosened related to density of individuals in the workplace and hiring. Access to such highly effective vaccines against SARS-CoV-2 has been a game changer and is allowing our study to return to full capacity.
JICR: What are the most exciting projects that you plan to dive into in the near future?
Emily Hemann: We are really excited about looking into the role of IFN-λ in programming memory immunity against influenza virus infection, and also to determine whether IFN-λ can augment CD8 immunity in the context of infection and vaccination, moving one step closer to how this could be relevant in a therapeutic setting. We are also working on understanding how IFN-λ regulates dendritic cell function. We have noticed some defects in dendritic cell function in the absence of IFN-λ signaling, but if we can start to figure out the mechanisms of how this is being regulated and whether or not these pathways are conserved in human dendritic cells, I think that will also be an exciting new avenue to see whether this is something that could move forward and potentially be used as a therapeutic in a human population, on top of making these basic science discoveries.
JICR: What is the most important advice you would give to young scientists starting their own research program?
Emily Hemann: Do not be afraid to ask for help from your colleagues and those around you. I think that most of us in science are used to working in groups, but many of the experiments we do and the expertise we gain are something we do on an individual basis. You are trying to carve out a niche in a scientific area for yourself. But especially when you are transitioning to starting your own research group, your colleagues can help you overcome some of the more critical challenges to starting a research program: things such as ordering and getting protocols approved and things you do not necessarily think about at different stages in your career. Interacting with your colleagues can also elevate your science and expertise through new collaborations. Transitioning from the mindset of defining yourself as your own research entity into developing a research group and plugging into those around you I think is something that is important to do as early as possible.
