{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T21:35:42Z","timestamp":1782509742810,"version":"3.54.5"},"reference-count":115,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/life15101575","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:31Z","timestamp":1760028871000},"page":"1575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cross-Priming and Cross-Tolerance After Intramuscular mRNA Vaccination for Viral Infections: Feasibility and Implications"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-5027","authenticated-orcid":false,"given":"Siguna","family":"Mueller","sequence":"first","affiliation":[{"name":"Center for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109762","DOI":"10.1016\/j.clim.2023.109762","article-title":"The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses","volume":"255","author":"Geckin","year":"2023","journal-title":"Clin. 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