# Cross-Priming and Cross-Tolerance After Intramuscular mRNA Vaccination for Viral Infections: Feasibility and Implications

## TL;DR

This review explores how intramuscular mRNA vaccines might activate CD8 T cells through a process called cross-presentation, which could explain their effects on unrelated infections.

## Contribution

The paper highlights the underappreciated role of cross-presentation in mRNA vaccines and its potential to induce cross-tolerance.

## Key findings

- Intramuscular mRNA vaccines may rely on cross-presentation by migratory antigen-presenting cells to activate CD8 T cells.
- Cross-presentation could lead to both specific immune responses and nonspecific effects like cross-tolerance.
- This process may explain some unexplained outcomes of mRNA vaccination, including effects on heterologous infections.

## 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.