Lobb et al. showed that IFN-I pretreatment of DCs in vitro abrogated DC uptake/expression of mRNA-LNPs, and that mRNA-LNP vaccination of mice induced IFN-I transiently. Prior disruption of IFN-I signaling enhanced splenic DC uptake/expression of vaccine, and CD8⁺ T cell priming. IFN-I signaling induced by GFP (mock) vaccination 24 hr prior to vaccination with antigen reduced DC uptake of mRNA-LNPs, and cDC1-dependent CD8⁺ T cell responses. Inhibition of IFNAR signaling alone enhanced effector function and tumor control by vaccine-induced CD8+ T cells, and restored antiviral responses in models not impacted by other virus-induced cytokines.
Contributed by Paula Hochman
ABSTRACT: Type I interferons (IFN) are key mediators of innate immune activation, promoting upregulation of costimulatory molecules and Major Histocompatibility Complex (MHC) I/II on antigen-presenting cells (APCs). However, IFN also suppress endogenous translation to restrict viral replication. Critically, IFN-stimulated APCs lose the capacity to acquire new antigens, making the timing of IFN signaling a crucial determinant of vaccine efficacy. Here, we show that both DC-specific loss of IFNα/β receptor (IFNαR) and transient blockade of IFNαR before vaccination enhances vaccine uptake and expression within DCs, improves CD8⁺ T cell priming, and leads to superior tumor control. We also demonstrate that IFN signaling before vaccination, triggered by prior infection or administration of a different vaccine, impairs dendritic cell uptake of mRNA-LNP vaccines and reduces the magnitude of vaccine-specific CD8⁺ T cell responses. These findings highlight the dual-edged nature of IFN signaling and offer a potential strategy for enhancing vaccine-induced immunity.
Author Info: (1) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (2) Department of Immunology and Microbiology, University of
Author Info: (1) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (2) Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (4) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (5) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (6) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (7) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (8) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (9) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. (10) Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA. stephen.ferris@health.slu.edu.
