Somatic mutations associate with clonal expansion of CD8 + T cells

• Published in: Science advances 2024-06, Vol.10 (23), p.eadj0787
• Main 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
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomedicine and Life Sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Female; Gene Frequency; Human Genetics; Humans; Immunology; Male; Middle Aged; Mutation; Phenotype; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; SciAdv r-articles; Single-Cell Analysis
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adj0787

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