Type I interferon restricts mRNA vaccine efficacy through suppression of antigen uptake in cDCs

🥉 Top 5% JournalJan 4, 2026NPJ vaccines

Type I interferon may reduce mRNA vaccine effectiveness by lowering antigen uptake in key immune cells

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Loss of the IFNα/β receptor in dendritic cells enhances vaccine uptake and T cell responses.

Dendritic cells lacking the IFNα/β receptor show improved uptake and expression of vaccines.
Enhanced CD8⁺ T cell priming is observed when IFNα/β receptor signaling is blocked prior to vaccination.
Prior infection or different vaccine administration can impair dendritic cell uptake of mRNA-LNP vaccines.
Increased IFN signaling before vaccination is associated with reduced vaccine-specific CD8⁺ T cell responses.
The timing of IFN signaling plays a critical role in vaccine efficacy.

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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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