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.
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Acknowledgements
Stephen T. Ferris is supported by the President’s Research Fund of Saint Louis University School of Medicine (S.F.). Elise Alspach, PhD, is supported by a Research Scholar Grant, RSG-24-1251974-01-IBCD, from the American Cancer Society (https://doi.org/10.53354/ACS.RSG-24-1251974-01-IBCD.pc.gr.193734), and is the recipient of a Cancer Research Institute CLIP Grant (CRI5509). We thank the NIH Tetramer Core Facility (NIH Contract 75N93020D00005 and RRID:SCR_026557) for providing H2-Kb chicken ova 257-264 SIINFEKL Monomer.
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Conceptualization: S.T.F., T.A.L., and A.D.; Methodology: S.T.F., T.A.L., E.A., and L.V.T.; Investigation: T.A.L., S.T.F., S.B., J.A.C., Y.D., and W.G.; Visualization: T.A.L. and S.T.F.; Funding acquisition: S.T.F.; Project administration: S.T.F. and R.J.D.; Supervision: S.T.F.; Writing—original draft: T.A.L. and S.T.F.; Writing—review & editing: T.A.L., S.T.F., E.A., L.V.T., and W.G.
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Lobb, T.A., Dickson, A., Guo, W. et al. Type I interferon restricts mRNA vaccine efficacy through suppression of antigen uptake in cDCs. npj Vaccines (2026). https://doi.org/10.1038/s41541-025-01362-z
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DOI: https://doi.org/10.1038/s41541-025-01362-z
