A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle–based mRNA vaccines
Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.
Authors
- Hiroshi Takayanagi (ORCID: https://orcid.org/0000-0002-1462-4127)
- Taku Ito-Kureha (ORCID: https://orcid.org/0000-0002-6239-9227)
- Kenta Nakano (ORCID: https://orcid.org/0000-0003-2617-1468)
- Takeshi Nitta (ORCID: https://orcid.org/0000-0003-2384-3062)
- Ryunosuke Muro
- Ken J. Ishii (ORCID: https://orcid.org/0000-0002-6728-3872)
- Kazuo Okamoto (ORCID: https://orcid.org/0000-0001-5855-5357)
- Masato Kubo
- Takuya Sugita
- Tadashi Okamura (ORCID: https://orcid.org/0000-0001-8457-1561)
- Kouji Kobiyama (ORCID: https://orcid.org/0000-0002-5846-4807)
- Hung Hiep Huynh
- Suqi Wang (ORCID: https://orcid.org/0009-0001-6783-3651)
Institutions
- Kanazawa University (JP)
- Tokyo University of Information Sciences (JP)
- Kyoto University (JP)
- University of California San Diego (US)
- National Center for Global Health and Medicine (JP)
- Kyoto University of Education (JP)
- National Institute of Animal Health (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1126/sciadv.aec7827
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Nakatomi Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Cancer Research Institute, Kanazawa University
- Kowa Life Science Foundation
- Secom Science and Technology Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Hamaguchi Foundation for the Advancement of Biochemistry
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Japan Society for the Promotion of Science