MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2<sup>+</sup> γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

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Publication Details

Journal
Science Immunology
Published
2025-08-29
DOI
https://doi.org/10.1126/sciimmunol.adu3337
Citations
7
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
5.58
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article

MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines

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7 citations
Science Immunology
Immune Cell Function and Interaction
5.58
article

MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines

Teresa Lambe, Rajeka Lazarus, Maheshi Ramasamy, Yama F Mujadidi, Vincenzo Libri, Helen Hill, Síle A. Johnson, Tanya Dinesh, Paul T. Heath, N. Kelly, Carl-Philipp Hackstein, Alice Bridges-Webb, Sue Charlton, Ali Amini, Nicholas M. Provine, Katie Jeffery, Eleanor Barnes, Paul Klenerman, Matthew D. Snape, Elizabeth Clutterbuck, Eloise Phillips, Adam Finn, Sam M. Murray, Parvinder K. Aley, Christina Dold, Lucy C. Garner, Donal Skelly, Daniela M. Ferreira, Alexander J. Mentzer, Andrea M. Collins, Philip Goulder, John Frater, Anni Jämsén, Lizzie Stafford, Xinxue Liu, Philippa Clare Matthews, Alexandra Deeks, Donal O’Shea, Jeremy Chalk, David W. Eyre, Lisa Frending, Mary Ramsay, Nisha Singh, Sagida Bibi, Andrew E. Hogan, Maria Fransiska Pudjohartono, Barbara Kronsteiner, R. H. Shaw, Tim James, Wanwisa Dejnirattisai, Nick Andrews, Saul N. Faust, Sandra Adele, Bassam Hallis, Susanna Dunachie, Tom Malone, J. Claire Cameron, Katia Sayaf, Lance C. W. Turtle, Gavin Robert Screaton, Beatrice Simmons, Robert C. Read, Anna England, David P. J. Turner, Patpong Rongkard, Amelia Heslington, Christopher Green, Paul Turner, Hannah Robinson, Christopher P. Conlon, Rachel White, Jonathan S Nguyen-Van-Tam, Arabella Stuart, Mohammad Ali, Melanie Greenland, Cristina Riquelme Vano, Emma Plesteda
article en
7 citations

Abstract

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes-mucosal-associated invariant T (MAIT) cells and Vδ2<sup>+</sup> γδ T cells-which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)-mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell-derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ-licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

Science ImmunologyVol. 10(110)
University College Dublin (IE), Siriraj Hospital (TH), Centre for Human Genetics (GB), National University of Ireland, Maynooth (IE), Mahidol University (TH), Nuffield Orthopaedic Centre (GB), University of Oxford (GB), Medawar Building for Pathogen Research (GB), St. Vincent's University Hospital (IE), National Children’s Research Centre (IE), Mahidol Oxford Tropical Medicine Research Unit (TH), Oxford BioMedica (United Kingdom) (GB), Oxford University Hospitals NHS Trust (GB), Technical University of Munich (DE)
Openalex Percentile: Top 4%
Immune Cell Function and Interaction
5.58
DOIOpen Access PDFOpenAlex
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