Somatic mutations associate with clonal expansion of CD8+ T cells

: 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

: 2024

: Science Advances

: Science advances

: Sci Adv

: eadj0787

: 10

: 23

: 2375-2548

DOI: https://doi.org/10.1126/sciadv.adj0787

: https://www.science.org/doi/10.1126/sciadv.adj0787

: 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 T_EMRA phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8⁺ T cell expansions without malignant transformation.

sciadv.adj0787.pdf

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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.