Edited and Reviewed by: Silvano Sozzani, Department of Molecular Medicine, Sapienza University of Rome, Italy
*Correspondence: Achille Broggi,
This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Type III interferons or IFN-λs, are composed of 4 members: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. IFN-λs are master protectors against mucosal viral infections due to the preferential expression of their cognate receptor, IFNLR1, to cells of epithelial lineage and to a restricted pool of immune cells. IFN-λ receptor activation induces intracellular signaling that overlaps with that of type I interferons (IFN-I) and culminates with the induction of Interferon-Stimulated-Genes (ISG) with antiviral functions. However, several studies have uncovered non-redundant functions of IFN-λs, compared to IFN-I, that go beyond viral restriction at epithelial barriers. In this topic, we highlighted several emerging aspects of IFN-λ biology, including: their ability to restrict non-viral infections, the mechanisms by which they modulate immune responses, and the enigmatic role of human IFN-λ4.
One of the defining characteristics of IFN-λs is their ability to induce a targeted response in the barrier epithelia without stimulating excessive immune cell recruitment which can lead to immunopathology. This property of IFN-λs makes them central regulators of inflammation during viral and non-viral diseases. On the one hand, in addition to inducing antiviral gene programs, IFN-λs can dampen immune cell-mediated inflammation and promote physiological intestinal epithelial cell functions. On the other hand, IFN-λs can fuel the immunopathology of inflammatory diseases by preventing cell differentiation and proliferation and thus dampening barrier repair. In this Research Topic,
The observation that IFN-λs modulate host inflammation opens new questions regarding their therapeutic applications in infectious diseases. In their original paper,
Overall IFN-λs’ ability to shape immunity is increasingly appreciated. Several contributions to this topic highlight the emerging role of IFN-λs as immune regulators and raise interesting questions, such as what are the differences between the mouse and human IFN-λs biology, and what other indirect connections between IFN-λs and immune responses exist.
IFN-λ4 was the latest addition to the IFN-λs family and its functions have been a matter of debate since its discovery. Although the
However, how IFN-λ4 drives detrimental responses during infection is still unknown. One step toward the answer comes from
Interferons have been classically viewed as potent antiviral cytokines. The induction of ISG inhibits the replication of viral pathogens by modifying intracellular biological processes necessary for pathogen dissemination. More recent studies have demonstrated that IFNs can also modify how cells respond to intracellular bacterial infections. In this Research Topic,
IFN-λs were historically believed to be a redundant addition to the interferon arsenal present in epithelial cells. Their originality resided in two critical differences 1) their receptor is specific to mucosal surfaces, and 2) they confer anti-viral activity with different kinetics compared to type I IFNs. We have now started to peel back the layers and reveal unique IFN-λs-specific functions that might be even more important than their primary anti-viral function. We now know that IFN-λs are excellent immune modulators involved in regulating the response to infectious agents, autoimmunity, and chronic inflammatory disorders. Finally, the biology of the shyest IFN-λ, IFN-λ4, is starting to be unraveled. However, our understanding of IFN-λ4 biology is in its infancy.
IFN-λs need to be studied beyond their canonical anti-viral functions as several pieces of evidence suggest that these cytokines have context-specific functions and act differently in different cell types. It is critical to understand how IFN-λs act in individual cell types and to integrate this understanding to define the role of IFN-λs at the tissue level as a mediator of intrinsic local protection and coordinator of tissue-specific immune cells.
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
AB is supported by the excellence initiative of Aix Marseille Universit.-A*Midex, a French “investissements d’Avenir” program: AMX-20-CE-01; the FRM amor.age de jeunes equipes grant AJE202010012468; and the ANR-JCJC grant “INTERMICI” ANR-21-CE15-0022. This work was supported by research grant starting package from the University of Florida, College of Medicine, to SB DMS was supported by the University of Manitoba, Natural Sciences and Engineering Research Council of Canada, Research Manitoba, Children's Hospital Research Institute of Manitoba and Canadian Institutes of Health Research (GA1- 177700). AF was supported by OSU funds for Advancing Research in Infection and Immunity.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.