CD8+ T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance

Aoki, Hiroyasu; Kitabatake, Masahiro; Abe, Haruka; Xu, Peng; Tsunoda, Mikiya; Shichino, Shigeyuki; Hara, Atsushi; Ouji-Sageshima, Noriko; Motozono, Chihiro; Ito, Toshihiro; Matsushima, Kouji; Ueha, Satoshi

doi:10.1016/j.celrep.2024.113887

Cited by 2 publications

References 69 publications

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Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

Binayke,

Zaheer,

Vishwakarma

et al. 2024

Journal of Medical Virology

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Emerging evidence shows increased humoral response post‐omicron surge, but research on T cell responses is limited. This study investigated the durability, magnitude, and breadth of SARS‐CoV‐2‐spike‐specific T cell responses in 216 two‐dose vaccinated individuals pre‐ and post‐omicron surge. Post‐surge samples showed enhanced T cell responses, indicating widespread asymptomatic exposure to omicron. Further analysis of 105 individuals with multiple exposures to SARS‐CoV‐2 through boosters or infections showed that post‐omicron, two‐dose vaccinated individuals had T cell responses comparable to those of COVID‐19 convalescents or boosted individuals. Additionally, we report cross‐reactive T cell responses against omicron sub‐variants, including BA2.86, remained strong, with preserved frequencies of spike‐specific stem‐cell‐like memory T cells. In silico prediction indicates that mutated epitopes of JN.1 and KP.2 retain over 95.6% of their HLA binding capability. Overall, our data suggests that T cell responses are sustained, enhanced, and cross‐reactive against emerging SARS‐CoV‐2 variants following symptomatic or asymptomatic omicron infection.

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Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

Binayke,

Zaheer,

Vishwakarma

et al. 2024

Journal of Medical Virology

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LAG-3 blockade reactivates the CD8⁺T cell expansion program to re-expand contracted clones in the tumor

Takahashi,

Tsunoda,

Aoki

et al. 2024

Preprint

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Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8+T cells in the tumor1,2. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we developed a multi-tumor mouse model system to track hundreds of expanding and contracting CD8+T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identified a transcriptomic signature in PD-1+Ly108+precursor exhausted cells3,4that strongly predicts rates of intratumoral clone expansion in mice and humans. We found that expression of the signature successfully stratifies melanoma patient outcomes to PD-1/PD-L1 blockade5,6. Downregulation of the signature precedes clone contraction – a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade – an FDA-approved therapy whose effects on CD8+T cell responses are currently unclear7, re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful ‘pan-immunotherapy’ signature for monitoring immunotherapies, including PD-1/PD-L1 and LAG-3 blockade, with implications for their future development.

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CD8+ T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance

Cited by 2 publications

References 69 publications

Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

LAG-3 blockade reactivates the CD8⁺T cell expansion program to re-expand contracted clones in the tumor

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CD8+ T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance

Cited by 2 publications

References 69 publications

Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

Understanding the landscape of the SARS‐CoV‐2‐specific T cells post‐omicron surge

LAG-3 blockade reactivates the CD8+T cell expansion program to re-expand contracted clones in the tumor

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LAG-3 blockade reactivates the CD8⁺T cell expansion program to re-expand contracted clones in the tumor