A1 Refereed original research article in a scientific journal
Somatic mutations associate with clonal expansion of CD8+ T cells
Authors: Lundgren, Sofie; Myllymäki, Mikko; Järvinen, Timo; Keränen, Mikko A. I.; Theodoropoulos, Jason; Smolander, Johannes; Kim, Daehong; Salmenniemi, Urpu; Walldin, Gunilla; Savola, Paula; Kelkka, Tiina; Rajala, Hanna; Hellström-Lindberg, Eva; Itälä-Remes, Maija; Kankainen, Matti; Mustjoki, Satu
Publisher: American Association for the Advancement of Science
Publication year: 2024
Journal: Science Advances
Journal name in source: Science advances
Journal acronym: Sci Adv
Article number: eadj0787
Volume: 10
Issue: 23
eISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.adj0787
Web address : https://www.science.org/doi/10.1126/sciadv.adj0787
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/456795693
Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in nonmalignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had a higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected lymphoid neoplasia. Single-cell sequencing revealed cytotoxic TEMRA phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.
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Funding information in the publication:
This research was funded with research grants from the European Research Council (M-IMM and STRATIFY projects), Academy of Finland, Sigrid Juselius Foundation, Cancer Foundation Finland, Blood Disease Research Foundation, and Instrumentarium Science Foundation. S.L. was supported by Biomedicum Helsinki Foundation and Finnish Medical Foundation.
