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.

Authors

Ilke Aernout, Thomas Ehouarne, Kevin Mwangi, Kia C Ferrell, Margo De Velder, Janne Swinnen, Aaron Verplancke, Laura Van Moortel, Margaux De Meyer, Patrick Willems, Lorenzo Franceschini, Karine Breckpot, Stefaan C De Smedt, Francis Impens, Caroline Demangel, Rein Verbeke, Ine Lentacker

Published in

Frontiers in immunology. Volume 17. Pages 1929726. Epub Oct 05, 2026.

Abstract

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-Guérin (BCG) vaccine. Here we investigated the immunological impact of incorporating alpha-Galactosylceramide (αGC) into mRNA lipid nanoparticles (mRNA-LNPs) as a vaccination strategy against Mycobacterium tuberculosis (Mtb), the pathogen causing TB. Using Mtb antigens ESAT-6 and Ag85B, we demonstrate that αGC-adjuvanted mRNA-LNPs induce controlled activation of invariant natural killer T (iNKT) cells, thereby reshaping vaccine-induced immunity. Specifically, αGC incorporation promoted the generation of CD44⁺CD69⁺CD62L^-CD4⁺ T cells in the spleen and altered the CD4⁺ T -helper (T_H) profile through the addition of modest T_H2 and T_H17 responses alongside robust T_H1 immunity. Furthermore, antigen-specific CD8⁺ 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-pull strategy combining intramuscular mRNA vaccination with local antigen instillation increased the frequency of antigen-specific lung-associated CD4⁺ T cells displaying a tissue residency-associated phenotype, with additional contribution of αGC adjuvantation to this response. In summary, these findings provide novel insights into αGC adjuvant-mediated immune modulation of mRNA vaccines and support further testing of protective efficacy of this approach against TB.

PMID:
42898436
Bibliographic data and abstract were imported from PubMed on 20 Oct 2026.

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