Somatic mutations and T-cell clonality in patients with immunodeficiency

Paula Savola, Timi Martelius, Matti Kankainen, Jani Huuhtanen, Sofie Lundgren, Yrjö Koski, Samuli Eldfors, Tiina Kelkka, Mikko A.I. Keränen, Pekka Ellonen, Panu E. Kovanen, Soili Kytölä, Janna Saarela, Harri Lähdesmäki, Mikko R.J. Seppänen, Satu Mustjoki*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

5 Citations (Scopus)
16 Downloads (Pure)


Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is, however, implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset CVID and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2,533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor b-sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in CVID, and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (2 patients), C5AR1 (2 patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, CVID patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.

Original languageEnglish
Pages (from-to)2757-2768
Number of pages12
Issue number12
Publication statusPublished - Dec 2020
MoE publication typeA1 Journal article-refereed


Dive into the research topics of 'Somatic mutations and T-cell clonality in patients with immunodeficiency'. Together they form a unique fingerprint.

Cite this