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 6

IFN-λ boosts CD4+ T cell function through CCR2+ inflammatory monocytes.

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IFN-λ boosts CD4+ T cell function through CCR2+ inflammatory monocytes. ...
(A–C) Ifnar–/– mice were infected with 104 PFU HSV-2 333 and administered PBS or IFN-λ 1 DPI (n = 5, 5). Data representative of 2 independent experiments. (A) Total vaginal cells were collected 5 DPI and stimulated with HSV-2 lysate for 24 hours. Proportion of IFN-γ+CD4+ T cells to total CD4+ cells. (B) Proportion of IFN-γ+CD8+ T cells to total CD8+ cells. (C) Total IFN-γ levels in supernatants. (D) Representative flow plots of CD11b+ DCs (CD45+/Ly6G–/CD3–/B220–/CD11b+/CD11c+/MHCII+) from unstimulated vaginal cells. (E) Total number of CD11b+ DCs 5 DPI (n = 5, 4). (F) Representative flow plots for Ly6ChiCCR2+ (CD45+/Ly6G–/CD3–/B220–/CD11b+/Ly6Chi/CCR2+) and Ly6CloCCR2– (CD45+/Ly6G–/CD3–/B220–/CD11b+/Ly6Clo/CCR2–) cells to assess MHC II gMFI. (G) Total number of Ly6ChiCCR2+ cells (n = 5, 4). (H) Total number of Ly6CloCCR2– cells. (I) MHC gMFI of Ly6ChiCCR2+ cells. (J) MHC gMFI of Ly6CloCCR2– cells. (K) Representative flow plots for comparing Ly6C and MHC II expression in CD11b+ cells. (L) Ifnar–/– mice infected with HSV-2 333 and administered IFN-λ were administered PBS or α-CCR2 daily (n = 4, 5). Data shown are representative of 2 independent experiments with similar results, except N, which is representative of 2 pooled experiments (n = 9, 9). (M) Viral titers. (N) IFN-γ levels in vaginal washes 5 DPI. (O) Total number of CD4+ T cells. (P) Total number of CD8+ T cells. (Q) Total number of Ly6ChiCCR2+ cells. (R) Total number of Ly6CloCCR2– cells. (S) Total number of CD11b+ DC cells. *P < 0.05, **P < 0.01 ***P < 0.0001, ****P < 0.00001. Statistical significance determined by repeated 2-way ANOVA with Šídák’s multiple comparisons test (M) or 2-tailed Student’s t test (A–C, E, G–J, and N–S). gMFI, geometric mean fluorescence intensity.