By Siguna Mueller
Center for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
Life2025, 15(10), 1575; https://doi.org/10.3390/life15101575
Abstract
The induction of robust CD8 T cell immunity after intramuscular (i.m.) mRNA vaccination has remained a challenge. Due to the limited presence of professional antigen-presenting cells (APCs) in muscle tissue, this route of administration tends to result in the transfection of muscle cells at the injection site with insufficient T cell activation capacity. The attraction of migratory APCs and related processes that lead to the acquisition of antigenic material from transfected non-APCs arises as a potential alternative to facilitate activation of CD8 T cells in the draining lymph nodes. This indirect pathway, known as antigen cross-presentation, has remained underappreciated for mRNA vaccines. This review provides a comprehensive analysis of this process. Due to the paucity of information available in this context, it also extrapolates from insights for antigen cross-presentation more generally and for traditional vaccines. Arguments are provided as to why this natural process in the context of pro-drugs, such as mRNA vaccines, may engender both specific and nonspecific responses and, in certain situations, evoke cross-tolerance rather than immunity. This widely unaccounted T cell activation process may, therefore, explain several key mysteries surrounding i.m. RNA vaccination, including its impact on heterologous infections. But it also raises numerous open questions that are clearly described.
Keywords:
mRNA vaccines; CD8+ T cell response; antigen cross-presentation; pro-drug; systemic effects; tolerance; specificity; off-target effects
Read the full paper: https://www.mdpi.com/2075-1729/15/10/1575