Somatic mutations and T-cell clonality in patients with immunodeficiency

Abstract

Common variable immunodeficiency 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 common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta 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 common variable immunodeficiency 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 (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency 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.

Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature

“…Some of the mutations, especially in white blood cells, may contribute to chronic inflammation and autoimmunity (15)(16)(17). This hypothesis is supported by the identification of somatic mutations in the circulating, cytotoxic CD8+ and CD4+ lymphocytes in RA, Felty's syndrome, aplastic anemia, multiple sclerosis, chronic graft-versus-host-disease (cGVHD) and common variable immune deficiency patients (16)(17)(18)(19)(20)(21)(22). The mutation harboring CD8+ lymphocyte clones in RA are stable, cytotoxic effector memory cells (16).…”

“…Calling of somatic variants from whole-exome sequencing data was performed similar to our previous study (17) and included mapping reads against GRCh38 reference with BWA (27) and calling variants with the GATK toolkit and MuTect2 (28).…”

T(o) be, or (not) to B, or both? Somatically mutated clonal T cells in common variable immunodeficiency and related immunodeficiencies

“…The germline mutations of the genes associated with CVID are heterogenous, and only 30-50% of patients with CVID were positive for germline mutations, such as NFKB1 in B-cell-signaling pathways, 5,6 while genetic abnormalities are still unknown in a significant proportion of CVID patients. In this study, Savola et al 4 identified germline TAC1 mutations in CVID patients, and STAT3 and ADA2 mutations in other immunodeficient patients. What role the somatically mutated T cells play in CVID and other immunodeficient states associated with these genetic backgrounds remains unclear.…”

“…In this issue of Haematologica, Savola et al 4 investigated the somatic mutations of T cells from patients with congenital immunodeficiency, including CVID, using deep amplicon sequencing with 2,355 gene panels and a T-cell receptor (TCR) b gene analysis to seek possible relation-ships between genetic alterations and T-cell abnormalities in these diseases. They found that 6 of 8 patients with CIVD harbored somatically mutated T cells and, in total, 59% of patients with congenital immunodeficiency were positive for somatic mutations in CD4 + or CD8 + T cells, which would be expected to have deleterious effects on the cellular functions of T cells (Figure 1).…”

“…Patients with immunodeficiency had more convergent, namely restricted, TCR b chain CDR3 sequences, although these were not specific to previously known Figure 1. Germline mutations, abnormalities of B cells and somatically mutated clonal T cells identified in common variable immunodeficiency and other immunodeficiencies by Savola et al 4 Savola et al 4 demonstrated somatic mutation of selected genes in the T cells of patients with CVID and related immunodeficiencies. Somatically mutated clonal T cells would lead to T-cell abnormalities and might contribute to the recurrence of infection due to hypogammaglobulinemia and B-cell lymphoproliferative disorders in patients with these immunodeficiencies.…”