Interferon-λ inhibits immunopathology and boosts T cell–mediated immunity in a mouse model of mucosal viral infection
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
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
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Research Article Immunology Infectious disease Inflammation

Interferon-λ inhibits immunopathology and boosts T cell–mediated immunity in a mouse model of mucosal viral infection

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

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Figure 4

IFN-λ treatment does not alter T cell priming.

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IFN-λ treatment does not alter T cell priming. (A–O) WT, Ifnar–/–, and I...
(A–O) WT, Ifnar–/–, and Ifnar–/– administered IFN-λ 1 DPI (n = 5, 5, 4) were infected with 104 PFU HSV-2 333. Data shown in A–G are representative of 2 independent experiments; H–L are representative of 3 independent experiments with similar results; and M–O are representative of 3 independent experiments pooled (n = 10, 14, 14). The dLN was collected 5 DPI. (A) Total number of cDCs (CD45+/B220–/CD3–/CD11c+/MHC II+/CD26+/CD64–). (B) Total number of moDCs (CD45+/B220–/CD3–/CD11c+/MHC II+/CD26–/CD64+). (C) Histograms for CD40, CD80, CD86, and MHC II for total DCs. (D) CD40 gMFI. (E) CD80 gMFI. (F) CD86 gMFI. (G) MHC II gMFI. (H) Total number of CD45+ cells. (I) Total number of CD3+ T cells (CD45+/CD3+). (J) Proportion of CD4+ T cells (CD45+/CD3+/TCRβ+/TCRγδ–/CD8–/CD4+) to total CD45+ cells. (K) Proportion of CD8+ T cells (CD45+/CD3+/TCRβ+/TCRγδ–/CD8+/CD4–) to total CD45+ cells. (L) Proportion of IFN-γ+CD4+ T cells to total CD4+ cells. (M) IFN-γ+CD8+ T cells to total CD8+ cells. (N) Proportion of L. IL-17A+CD4+ T cells to total CD4+ cells. (O) IFN-γ levels in the supernatants. *P < 0.05, **P < 0.01. ***P < 0.001. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple comparisons test. gMFI, geometric mean fluorescence intensity.