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Editor's note
Open Access | 
10.1172/JCI211631
IFN-λ fine tunes protective immunity during mucosal viral infection
Pablo Penaloza-MacMaster, Associate Editor
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Published October 15, 2026 - More info
J Clin Invest. 2026;136(20):e211631. https://doi.org/10.1172/JCI211631.
© 2026 Penaloza-MacMaster et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Interferon lambda (IFN-λ) has emerged as a critical inducer of immune regulation in addition to its mucosal antiviral properties. However, the cellular and molecular mechanisms that govern its dual role during viral infections remain unclear. Here, we discovered that mucosal delivery of IFN-λ abrogates the herpes simplex virus type 2–induced (HSV-2-induced) vaginal tissue pathology observed in the absence of type I IFN signaling, through drastically inhibiting IL-6 production. At the same time, we demonstrated that IFN-λ rescued local production of CD4+ T cell–dependent IFN-γ, which is essential for protection against the development of toxic megacolon following genital HSV-2 infection. Mechanistically, we found that IFN-λ enhances the differentiation of CCR2+Ly6Chi cells into monocyte-derived antigen-presenting cells, thereby boosting T cell responses. In vivo depletion of CCR2+ cells abrogated this phenomenon. Together, these findings suggest that IFN-λ orchestrates a potent antiviral response, inhibiting hyperinflammatory responses while selectively augmenting effector T cell function. This study positions IFN-λ as a promising therapeutic candidate for enhancing local antiviral immunity and offers new insights into the regulation of immune responses in the context of mucosal viral infections.
Authors
Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar
Unlike the broadly expressed type I–IFN receptor, which sensitizes most cells in in the body to IFN-I, expression of the IFN-λ receptor is restricted to epithelial surfaces and select immune cell populations, allowing IFN-λ to limit viral replication mostly at epithelial barriers (1–5). IFN-λ can also provide antiviral protection, typically with less inflammation than type I IFN (6). Coordinated antiviral responses are particularly critical at mucosal or epithelial barriers, as these are the primary entry sites for many viruses, including herpes simplex virus type 1 and 2 (HSV-1 and -2), Epstein-Barr virus, human papilloma virus (HPV), and HIV-1, which can also induce detrimental inflammation. While the antiviral effects of IFN-λ at mucosal sites are well documented, the mechanism by which IFN-λ balances immune protection and immunopathology at mucosal sites is still not well understood.
In this issue of the JCI, Feng and colleagues investigated the antiviral and immunoregulatory functions of IFN-λ using genital HSV-2 infection in Ifnar1-deficient mice, which exhibit uncontrolled viral infection and severe immunopathology (7). Mucosal administration of IFN-λ shortly after viral infection reduced viral loads while also ameliorating immune-driven epithelial injury. Mechanistically, IFN-λ was shown to inhibit IL-6 production while rescuing production of CD4+ T cell–dependent IFN-γ. IFN-λ also enhanced the generation of monocyte-derived antigen presenting cells, resulting in improved T cell responses. Importantly, depletion of CCR2+ cells abrogated this effect, suggesting a critical role for CCR2+ cells. The findings suggest that IFN-λ can be an effective therapeutic candidate for improving antiviral responses at mucosal barrier sites, while tightly regulating detrimental inflammatory responses that often accompany viral infections.
Feng et al.’s study is important because robust antiviral protection and immunopathology (typically caused by T cell–mediated tissue damage) often occur in tandem, and their data suggest that IFN-λ can partially decouple these two seemingly inextricable processes, in part by regulating IL-6 and CD4+ T cell–dependent production of IFN-γ. In summary, IFN-λ may be best understood not simply as a less inflammatory IFN, but as an important immune regulator of mucosal antiviral immunity with therapeutic potential against mucosal infections.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)