Ivan Zanoni : Type III interferons control intestinal inflammation

Key Speakers

Assistant Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital

The gastrointestinal tract is composed of a single layer of epithelial cells that separates the inside of the body from a complex and vast community of harmless micro-organisms (the microbiome) that live in the intestine and provide essential functions to the host. Underneath the epithelial lining is the largest population of immune cells in the mammalian body that serves as a critical monitor of these micro-organisms sensing the presence of potential disease-causing pathogens.

Inflammatory bowel disease (IBD) is thought to result when the immune system inappropriately responds to the microbiome. The immune signals that recognize and respond to bacterial and viral components of the microbiome are incompletely understood. Interferons (IFN) play a critical role in this process with diverse activities but are most known for their inherent anti-viral activities.

IFNs are divided into three classes: type I, type II IFNs and the more recently identified type III IFNs or IFN-λs. Most studies investigating the relationship of IFNs and IBD have focused on the relevance of type I IFNs. The cellular targets of IFN-λs are much more limited and defined, compared to those of type I IFNs, because the specific receptor for IFN-λ, IFNLR1, is almost exclusively expressed in epithelial cells.

Here, we report that neutrophils are the only immune cells that respond to IFN-λs. We found that, besides inducing ISG transcription, IFN-λs (but not type I IFNs) specifically activate a transcriptional-independent signaling pathway that dampens the most potent tissue damaging functions of neutrophils. In mice, IFN-λs are elicited by enteric viruses and act on neutrophils to diminish oxidative stress and intestinal damage. Thus, IFN-λs act as unique immunomodulatory agents by modifying transcriptional and non- transcriptional neutrophil responses, which may permit a controlled development of the inflammatory process.