Evaluation of T Cell Repertoire in Primary Immunodeficiencies With Dna Repair Defects

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Abstract Inborn errors of immunity include multiple genetic abnormalities affecting different components of the innate and adaptive immune systems. More than 450 genes have been described so far including DNA repair defects which may result in predisposition to infections, but also malignancies, neurologic abnormalities and growth retardation. The group of patients with DNA repair and methylation defects exhibit impaired adaptive immunity, which increases susceptibility to infections due to impaired repertoire diversity. In this context, we aimed to investigate the TCRvβ repertoire and its interaction with clinical entities in a group of IEI patients with DNA repair defects including ATM, DCLRE1C, DNA-PRKDC, DNA ligase-4, and BLM. Thirty-nine patients with evidence of DNA repair defects and radiosensitivity and 15 age-matched healthy controls were included in this study. Peripheral lymphocyte subset and TCR-vβ repertoire analyses were performed by flow cytometry. To contrast TCR-repertoire in patients with DNA repair defects to healthy controls, we extracted data on lymphocyte phenotype, thymic function, immunoglobulins, and analysis of the TCRvβ repertoire from a prior study. The entire TCR-vβ repertoire was detected in all patients. However, compared with the control group, 9 of 24 clones (37.5%) were statistically significantly lower, whereas only 3 clones had high levels (p < 0.05). In addition, 62.5% of all clones had lower values than the control group. Some unique vβ clones have been associated with some clinical entities. Clonotypes associated with infections, autoimmunity and lymphoid proliferation were detected in the patient group. Lower TCR-vβ-9 and TCR-vβ23, higher TCR-vβ7.2 were detected in the patients with pneumonia (n = 13) (respectively p = 0.018, p = 0.044 p = 0.032). In addition, AT patients with pneumonia (n = 10) had a lower TCR-vβ-9 clone than patients without pneumonia (n = 25) (p = 0.008). In summary, we observed skewed clonal proliferation of most TCR-vβ clones in DNA repair defects, especially AT. In addition, our study demonstrated that some TCR-vβ clones might be predictive of some clinical entities. To further investigate the impact of the diversity of the TCR repertoire on the clinical phenotype, future studies should focus on the analysis of naïve and memory T cells, the detection of the source of oligoclonality, and the relationship between clonality and clinical entities.

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