{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:54:21Z","timestamp":1791179661807,"version":"4.1.0"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Tuberculosis (TB) remains the leading cause of death from a single infectious agent worldwide, highlighting the need for improved vaccines beyond the limited protection currently provided by the Bacillus Calmette-Gu\u00e9rin (BCG) vaccine. Here we investigated the immunological impact of incorporating alpha-Galactosylceramide (\u03b1GC) into mRNA lipid nanoparticles (mRNA-LNPs) as a vaccination strategy against\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb), the pathogen causing TB. Using Mtb antigens ESAT-6 and Ag85B, we demonstrate that \u03b1GC-adjuvanted mRNA-LNPs induce controlled activation of invariant natural killer T (iNKT) cells, thereby reshaping vaccine-induced immunity. Specifically, \u03b1GC incorporation promoted the generation of CD44\n                    <jats:sup>+<\/jats:sup>\n                    CD69\n                    <jats:sup>+<\/jats:sup>\n                    CD62L\n                    <jats:sup>-<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the spleen and altered the CD4\n                    <jats:sup>+<\/jats:sup>\n                    T -helper (T\n                    <jats:sub>H<\/jats:sub>\n                    ) profile through the addition of modest T\n                    <jats:sub>H<\/jats:sub>\n                    2 and T\n                    <jats:sub>H<\/jats:sub>\n                    17 responses alongside robust T\n                    <jats:sub>H<\/jats:sub>\n                    1 immunity. Furthermore, antigen-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell responses against ESAT-6 and Ag85B were observed exclusively in the genetically diverse CB6F1\/J mouse model, highlighting the importance of host genetic background in evaluating mRNA vaccine immunogenicity after homologous vaccination strategies. Finally, we demonstrate that using a heterologous prime\u2013pull strategy combining intramuscular mRNA vaccination with local antigen instillation increased the frequency of antigen-specific lung-associated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells displaying a tissue residency-associated phenotype, with additional contribution of \u03b1GC adjuvantation to this response. In summary, these findings provide novel insights into \u03b1GC adjuvant-mediated immune modulation of mRNA vaccines and support further testing of protective efficacy of this approach against TB.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1929726","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:31:54Z","timestamp":1791178314000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Alpha-galactosylceramide as mRNA vaccine adjuvant modulates cellular immunity against tuberculosis and contributes to antigen-specific lung-associated T cells with a TRM-associated phenotype following prime-pull strategy"],"prefix":"10.3389","volume":"17","author":[{"given":"Ilke","family":"Aernout","sequence":"first","affiliation":[{"name":"Laboratory of Physical Pharmacy and General Biochemistry, Department of Pharmaceutics, Ghent Research Group on Nanomedicines, Ghent 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France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margo","family":"De Velder","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Pharmacy and General Biochemistry, Department of Pharmaceutics, Ghent Research Group on Nanomedicines, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne","family":"Swinnen","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Pharmacy and General Biochemistry, Department of Pharmaceutics, Ghent Research Group on Nanomedicines, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Verplancke","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Pharmacy and General Biochemistry, Department of Pharmaceutics, Ghent Research Group on Nanomedicines, Ghent University","place":["Ghent, Belgium"]},{"name":"Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Van Moortel","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Medicine, Ghent University","place":["Ghent, Belgium"]},{"name":"Vlaams Instituut voor Biotechnologie (VIB) Center for Medical Biotechnology, VIB","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaux","family":"De Meyer","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Medicine, Ghent University","place":["Ghent, Belgium"]},{"name":"Vlaams Instituut voor Biotechnologie (VIB) Center for Medical Biotechnology, VIB","place":["Ghent, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Willems","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Medicine, Ghent University","place":["Ghent, 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