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 3

IFN-λ treatment boosts CD4+ T cell–mediated immunity to infection.

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IFN-λ treatment boosts CD4+ T cell–mediated immunity to infection. (A–I)...
(A–I) Ifnar–/– mice were infected with 104 PFU HSV-2 333 and administered PBS or IFN-λ (n = 9, 8). Data representative of 2 pooled experiments, except C, which is representative of 2 experiments with similar results (n = 5, 5). (B) IFN-γ levels in vaginal washes 5 DPI. (C) CXCL9 levels. (D) CXCL10 levels. (E) Total number of CD45+ cells in the vaginal tissue. (F) Total number of T cells (CD45+/Ly6G–/CD3+). (G) Total number of CD4+ T cells (CD45+/Ly6G–/CD3+/TCRβ+/TCRγδ–/CD8–/CD4+). (H) Total number of CD8 T cells (CD45+/Ly6G–/CD3+/TCRβ+/TCRγδ–/CD8+/CD4–). (I) Total number of γδ+T cells (CD45+/Ly6G–/CD3+/TCRβ–/TCRγδ+). (J–P) Ifnar–/– mice were administered normal drinking water and PBS, FTY720 and PBS, normal drinking water and IFN-λ, or FTY720 and IFN-λ (n = 4, 5, 4, 4). Data representative of 2 independent experiments, except K and M, which are representative of 2 pooled experiments (n = 8, 5, 9, 9). (K) Rates of megacolon 5 DPI. (L) Viral titers. (M) IFN-γ levels. (N) Total number of CD4+ T cells. (O) Total number of CD8+ T cells. (P) Total number of TCRγδ+ cells 5 DPI. (Q–W) Ifnar–/– mice treated with IFN-λ 1 DPI intravaginally were administered PBS, α-CD4, IFN-λ, or α-CD4+IFN-λ (n = 5, 4, 5, 5). Data representative of 2 independent experiments, except R and T, which are representative of 2 pooled experiments (n = 10, 5, 10, 10). (R) Rates of megacolon 5 DPI. (S) Viral titers. (T) IFN-γ levels. (U) Total number of CD4+ T cells. (V) Total number of CD8+ T cells. (W) Total number of TCRγδ+ cells. *P < 0.05, **P < 0.01. Statistical significance determined by 2-tailed Student’s t test (B and E–I), repeated measures 2-way ANOVA with Šídák’s multiple comparisons test (C, D, L, and S), and ordinary 2-way ANOVA with Šídák’s multiple comparisons test (M–P and T–W).