Paradoxes of cellular immune responses evoked by mRNA injections - fostered by cross-priming and cross-tolerance but at a high price

A complete understanding of the immunological mechanisms of the mRNA vaccines has remainedelusive. This article focuses on key questions that demonstrate the limits of our comprehension ofCytotoxic T Lymphocytes (CTL) activation and details paradoxical observations related to the immuneresponse evoked. In August 2024, a study published in Nature Communications provided vital insights into innate immune processes triggered by the mRNA COVID-19 injections, and how they are linked to spike-specific cellular immune responses. Some of their findings have remained overlooked. While they offer a general framework of early immune activation, their enrichment of mRNA vaccine transcripts in injection-site fibroblasts indicate a pivotal role of Class I MHC processing and presentation of exogenous antigens. For mRNA vaccines, the potential of cross-presentation is largely under-appreciated. Their mechanism of CTL activation widely presumes the canonical MHC-I pathway, following generation of the endogenous vaccine antigen and their processing and presentation by professional antigen-presenting cells (APC), and facilitated by appropriate co-stimulation, despite the stymied 1-methylpseudouridine modification to reduce innate responses. Here, several arguments are provided that make mRNA vaccines particularly prone to the alternative pathway, whereby certain APCs, via uptake of vaccine or self-antigens, or those of other infections, can effectively evoke CTL response induction. These mechanisms underlying cross-presentation of exogenous antigens disprove the notion that the T cell response is specific to the vaccine antigen alone, in line with the published effects seen of the mRNA COVID-19 injections to heterologous infections where they appear to either enhance or dampen immune responses. Reasons are provided why injection-induced cross-tolerance may play a substantial role in inducing peripheral tolerance both to SARS-CoV-2 and heterologous infections. In all, cross-priming or cross-tolerance evoked by the mRNA injections may offer explanations to some of the main open questions related to this platform but also raise substantial concerns of clinical and environmental ramifications.