Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
Sci Adv. 2024 Jun 7;10(23):eadj0787. 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.
体细胞突变可导致癌症，但也与免疫性疾病和细胞治疗有关。非恶性 T 细胞中的突变谱尚不清楚。在这里，我们研究了 90 名血液系统和免疫性疾病患者的 CD4 和 CD8 T 细胞中的体细胞突变，并使用 T 细胞受体（TCR）和单细胞测序将突变与 T 细胞扩增和表型联系起来。CD8 细胞的突变负担高于 CD4 细胞。值得注意的是，CD8 T 细胞中非同义变异的最大等位基因变异频率（VAF）高于同义变体，表明非随机发生。CD8 T 细胞中非同义 VAF 与 TCR 频率强烈相关，但与年龄无关。我们鉴定了对 T 细胞功能至关重要的途径中的突变，这些途径通常会影响淋巴肿瘤。单细胞测序揭示了突变 T 细胞的细胞毒性 T 表型。我们的研究结果表明，体细胞突变导致 CD8 T 细胞扩增而不发生恶性转化。
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