The type I IFN-IL-27 axis promotes mRNA vaccine-induced CD8+ T cell responses
Phan, A. T.; Aunins, E.; Cruz-Morales, E.; Dwivedi, G.; Bunkofske, M.; Eberhard, J. N.; Aldridge, D. L.; Said, H.; Banda, O.; Tam, Y.; Christian, D. A.; Vonderheide, R. H.; Kedl, R. M.; Weissman, D.; Alameh, M.-G.; Hunter, C. A.
Show abstract
The ability of lipid nanoparticle (LNP)-delivered mRNA vaccines to induce type I IFNs is critical to promote CD8+ T cell responses. The studies presented here indicate that immunization with nucleoside modified mRNA-LNP vaccines drives myeloid cell expression of the cytokine IL-27, which acts on antigen-specific CD8+ T cells to sustain T cell expansion. In vitro and in vivo studies revealed that type I IFN signaling is necessary for mRNA-LNP-induced IL-27 production, that immunization failed in IL-27 KO mice, and that immunization of IFNAR1-deficient mice with mRNA-LNP particles that also encode IL-27 mRNA restored antigen-specific CD8+ T cell responses. In addition, IL-27 mRNA-LNPs served as an adjuvant that improved cytolytic CD8+ T cell responses and the therapeutic efficacy of mRNA-LNPs to drive anti-pathogen and anti-tumor immunity. These studies highlight the central role of IL-27 in mRNA-LNP induced CD8+ T cell responses and the ability of this cytokine to augment the functionality of the CD8+ T cell response for prophylactic or therapeutic immunization.
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