Elucidating the role of damage recognition pathways in dendritic cell processing of mRNA vaccines

Abstract

mRNA vaccines represent a transformative advancement in immunology, largely due to their ability to stimulate robust immunity via lipid nanoparticle (LNP) delivery. A unique aspect of their effectiveness involves the specialized activity of conventional dendritic cells, particularly the cDC1 subset, which excels in antigen uptake, processing, and cross-presentation through MHC-I. This function is central to activating CD8+ T cells and driving a potent immune response. cDC1s are particularly efficient at cross-presenting antigens due to high expression of pattern recognition receptors (PRRs), such as Clec9A, and production of a unique cytokine and chemokine profile, both crucial for priming effective T-cell responses. Despite these advantages, mRNA vaccines face significant challenges due to the instability of mRNA and limited understanding of the molecular mechanisms governing mRNA processing in dendritic cells, particularly within cDC1s. Addressing these gaps could significantly enhance the efficacy and stability of mRNA vaccines, allowing for tailored immunogenic responses and optimized vaccine formulations. This progress would facilitate the development of next-generation vaccines that are adaptable to rapidly evolving pathogens and tailored to target complex diseases like cancer. Consequently, this study focuses on developing an in vitro model to investigate mRNA vaccine processing in cDC1, aiming to deepen insights into their cellular dynamics and optimize the resilience and effectiveness of mRNA-based immunization.