Sustained antigen-specific CD8+ T cell immunity post-mRNA booster requires notch pathway activation

  • J Immunol. 2026 Jun 7;215(6):vkag074. doi: 10.1093/jimmun/vkag074.
Takuto Nogimori  1 ,  Yoshinori Okina  1 ,  Yuji Masuta  1 ,  Mayu Kumamoto  1  2 ,  Tomoka Matsuura  3  4 ,  Natsuko Kaku  4  5 ,  Satoko Ohfuji  3  4 ,  Tetsuo Kase  3  4 ,  Kyoko Kondo  6 ,  Yu Nakagama  4  5 ,  Sachie Nakagama  4  5 ,  Yuko Nitahara  4  5 ,  Shokichi Takahama  1 ,  Hiroshi Kakeya  4  7  8 ,  Victor Appay  9 ,  Wakaba Fukushima  3  4  8 ,  Yasutoshi Kido  4  5  8 ,  Takuya Yamamoto  1  2  10
Affiliations
  • 1. Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka, Japan.
  • 2. Laboratory of Aging and Immune Regulation, Graduate School of Pharmaceutical Sciences, The University of Osaka, Osaka, Japan.
  • 3. Department of Public Health, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
  • 4. Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
  • 5. Department of Virology and Parasitology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
  • 6. OMU Core Facilities Life Sciences Section, Osaka Metropolitan University, Osaka, Japan.
  • 7. Department of Infection Control Science, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
  • 8. Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Japan.
  • 9. ImmunoConcEpT, University of Bordeaux, Bordeaux, France.
  • 10. Department of Virology and Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan.
PMID: 42258807 DOI: 10.1093/jimmun/vkag074
Abstract

Messenger RNA (mRNA) vaccines effectively induce protective immunity, but antigen-specific CD8+ T cell responses exhibit limited persistence. In this study, we aimed to assess CD8+ T cell responses following a third dose of the Pfizer BNT162b2 COVID-19 vaccine and identify factors contributing to their longevity. Using HLA tetramers, we analyzed antigen-specific CD8+ T cells in 141 vaccinated individuals (86.5% female) and identified 2 groups: those with strong responses (strong group) and those with weak responses (weak group) 6 mo after the third mRNA vaccination. Transcriptomic analysis revealed that Notch signaling was upregulated in the strong group, and in vitro, the inhibition of Notch signaling significantly reduced CD8+ T cell expansion. These findings suggest that Notch signaling may contribute to maintain long-term antigen-specific CD8+ T cell responses following mRNA vaccination. Targeting this pathway could offer novel strategies for enhancing vaccine-induced cellular immunity and long-lasting protection.

Keywords
mRNA vaccine; memory T cells; notch signaling; spike-specific CD8+ T cells.
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