The adjuvant effect of an Il12 mRNA-LNP reveals a role for CD4+ T cell-dependent DC licensing in the CD8+ T cell response to mRNA vaccination 2331202

Abstract Introduction The use of mRNA lipid nanoparticles (mRNA-LNPs) provides a modular platform that allowed for rapid development of vaccines against SARS-CoV-2. Previous studies showed that the CD8+ T cell response generated by these vaccines is independent of CD4+ T cell help, type I conventional dendritic cells and IL-12. However, inclusion of an Il12 mRNA-LNP in an mRNA-LNP vaccine led to enhanced expansion of vaccine-specific CD8 T cells that were more functional upon restimulation. The signals involved in generating a T cell response to mRNA vaccination are incompletely understood, and the inclusion of additional mRNA components further complicates our understanding of these processes. Methods Mixed transfer of WT and IL-12R deficient OT-I T cells were used to assess the role of direct IL-12 signaling on CD8+ T cells. CD40L deficient, cDC1 deficient and CD4+ T cell depleted mice were used to assess the contribution CD4+ T cell dependent DC licensing to CD8+ T cell responses. Spatial transcriptomic analysis of lymph nodes was performed to assess early differences in mice given a standard vaccine or IL-12 adjuvanted vaccine. Results The use of IL-12R deficient OT-I T cells shows that the effects of IL-12 on CD8+ T cell expansion are independent of the ability of CD8+ T cells to respond to IL-12. Rather, spatial transcriptomic data reveals enhanced co-stimulatory protein and receptor expression that persist longer in IL-12 adjuvanted vaccination than in vaccination with standard mRNA-LNP. Incorporation of IL-12 results in enhanced effector CD4+ T cell responses, and we find that enhanced CD8+ T cell expansion is entirely dependent on CD4+ T cells, cDC1s, and CD40L. Conclusion Our data sets suggest that IL-12 induces CD4+ T cells to promote DC licensing via CD40-ligand and this process mediates the enhanced expansion of CD8+ T cells. Thus, the ability of an IL-12 mRNA adjuvant to amplify vaccine-induced CD8+ T cells relies on the engagement of pathways that are otherwise not engaged by standard mRNA vaccination. Funding Source Basser Center for BRCA Topic Categories Vaccines and Immunotherapy (VAC)