Somatic mutations associate with clonal expansion of CD8 + T cells

Author:

Lundgren Sofie12ORCID,Myllymäki Mikko12,Järvinen Timo123ORCID,Keränen Mikko A. I.124ORCID,Theodoropoulos Jason12ORCID,Smolander Johannes12ORCID,Kim Daehong12ORCID,Salmenniemi Urpu45ORCID,Walldin Gunilla6ORCID,Savola Paula127,Kelkka Tiina12ORCID,Rajala Hanna124ORCID,Hellström-Lindberg Eva6ORCID,Itälä-Remes Maija5,Kankainen Matti123ORCID,Mustjoki Satu128ORCID

Affiliation:

1. Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.

2. Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.

3. Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

4. Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.

5. Stem Cell Transplantation Unit, Turku University Hospital, Turku, Finland.

6. Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

7. Department of Clinical Chemistry, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

8. ICAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

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