Defining the cellular and molecular mechanisms regulating type III interferon responses

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Proteins known as cytokines act as messengers for cells to `talk' to each other whether during periods of homeostasis, inflammation or an active infection. One family of cytokines my lab studies, interferons (IFNs), were discovered first in 1957 (type I), and are well-known for their critical role in inhibiting virus replication and spread. Another antiviral IFN family member, type III IFNs (IFN-lambdas (L)), were discovered 46 years later than type I IFNs, therefore multiple fundamental questions have yet to be answered outside of protecting epithelial cells at mucosal barriers. I recently published that new human immune cell types directly respond to type III IFNs, which ultimately affects their responses to various stimuli. In addition, major fundamental gaps in knowledge exist in type III IFN receptor biology, especially regarding the unique type III IFN receptor subunit IFN-LambdaR1. In this proposed research program, my HQP and I will combine multiple approaches and techniques related to immunology, cell biology, biochemistry, imaging, and molecular biology to address three distinct short-term objectives with the long-term goal to understand how type III IFN responses are regulated at the cellular and molecular level. In the first 5 years, my HQP will identify signals at the protein and DNA level that affect type III IFN receptor expression. Second, we will expand on our previous work to determine novel pathways induced by type III IFNs in immune cells that are unique and potentially independent of their antiviral activity. Lastly, we will visualize what happens immediately after type III IFNs bind their receptor in individual immune cells. Knowledge generated from my research program will provide novel insights into a much-understudied family of cytokines to answer fundamental questions about type III IFN signaling and receptor biology. The proposed work will also reveal new immunological and regulatory pathways downstream of IFNs, including potential crosstalk between family members. Our work will also benefit Canada through the training of HQP in various cutting-edge techniques within an emerging field of immunology that will provide them with the appropriate expertise to excel as scientific leaders in their future careers.