mRNA vaccines engage unconventional pathways in CD8⁺ T cell priming

Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8⁺ T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens^1-4. However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8⁺ T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8⁺ T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8⁺ T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8⁺ T cells against antigens not encoded by the vaccine.