BNT162b2 mRNA Vaccination Activates Spike-Reactive Regulatory T Cells in Humans

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ID: 326300
2026
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Abstract
Studies using mouse models of viral infection have shown that viral antigen-reactive regulatory T cells play multiple context-dependent roles, including attenuating the immune response against the pathogen and limiting inflammatory damage. By contrast, evidence for the presence and function of viral antigen-specific Tregs in humans remains very limited. Here, we investigated whether BNT162b2 mRNA COVID-19 vaccination activates spike (S)-reactive Tregs in healthy adults. We performed an integrated analysis combining scRNA-seq, TCR repertoire profiling, and flow cytometry of activation-induced marker (AIM) expressing S-reactive CD4+ T cells isolated from PBMCs cultured with trimeric S protein. We found that CD39+ cells co-expressing CTLA4 and TIGIT within the S-reactive AIM+ CD4+ T cell population were preferentially enriched for Tregs relative to their CD39- counterparts. In subjects vaccinated with BNT162b2 mRNA vaccine, the frequencies of CD39+CTLA4+ and CD39+TIGIT+ S-reactive Treg-like cells were significantly increased following vaccination. Using scRNA-seq, we identified two FoxP3+ Treg clusters among S-reactive CD4+ T cells: one characterized by IFN-activated gene signatures and another by high HLA class II, CD39 and CTLA4 expression. Both subsets were transcriptionally activated following vaccination, with upregulation of genes associated with T cell activation and inflammatory cytokines including TNF and IFNG. Consistent with these findings, flow cytometry detected increased proportions of CD39+ and FoxP3+ S-reactive Tregs expressing IFN-γ and/or TNF-α following vaccination. Collectively, these findings support a model in which BNT162b2 mRNA vaccination activates both an S-reactive effector T cell response and a Treg response, suggesting Treg co-induction may be critical for balancing antiviral immunity with immunoregulation.
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Authors Naila Shinwari, Xinxin Xue, Dongyun Lu, Celine Chua, Yayoi Iwamoto, Yuki Masuo, Sho Sekito, Daisuke Akiyama, Yasuhiro Murakawa, Takao Hashiguchi, 勇夫 伊藤, Hiroyuki Yoshitomi, Hideki Ueno
Journal international immunology
Year 2026
DOI
10.1093/intimm/dxag045
URL
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