Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

P Savola; T Kelkka; H L Rajala; A Kuuliala; K Kuuliala; S Eldfors; P Ellonen; S Lagström; M Lepistö; T Hannunen; E I Andersson; R K Khajuria; T Jaatinen; R Koivuniemi; H Repo; J Saarela; K Porkka; M Leirisalo-Repo; S Mustjoki

doi:10.1038/ncomms15869

Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

Nat Commun. 2017 Jun 21:8:15869. doi: 10.1038/ncomms15869.

Authors

P Savola^{1

2}, T Kelkka^{1

2}, H L Rajala¹, A Kuuliala³, K Kuuliala³, S Eldfors⁴, P Ellonen⁴, S Lagström⁴, M Lepistö⁴, T Hannunen⁴, E I Andersson¹, R K Khajuria¹, T Jaatinen⁵, R Koivuniemi⁶, H Repo³, J Saarela⁴, K Porkka¹, M Leirisalo-Repo⁶, S Mustjoki^{1

2}

Affiliations

¹ Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Centre, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
² Department of Clinical Chemistry and Hematology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
³ Bacteriology and Immunology, Medicum, University of Helsinki, Haartmaninkatu 3, FIN-00290 Helsinki, Finland.
⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
⁵ Histocompatibility Testing Laboratory, Finnish Red Cross Blood Service, Kivihaantie 7, FIN-00310 Helsinki, Finland.
⁶ Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.

Abstract

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age Factors
Aged
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / pathology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / pathology
CD4-Positive T-Lymphocytes / physiology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / physiology
Case-Control Studies
Female
Genes, T-Cell Receptor beta
High-Throughput Nucleotide Sequencing
Humans
Interferon Regulatory Factor-1 / genetics
Interferon Regulatory Factor-1 / immunology
Male
Middle Aged
Mutation*
Prospective Studies
Signaling Lymphocytic Activation Molecule Family / genetics
Signaling Lymphocytic Activation Molecule Family / immunology
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / pathology*
T-Lymphocytes, Cytotoxic / physiology

Substances

IRF1 protein, human
Interferon Regulatory Factor-1
SLAMF6 protein, human
Signaling Lymphocytic Activation Molecule Family