Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence

Ruud W J Meijers,Dennis Tielemans,Jacques J M Van Dongen,Mirjam Van Der Burg,Katarzyna Dzierzanowska-Fangrat,Bob A C Van Turnhout,Anton W Langerak,Krystyna H Chrzanowska,Magdalena Zborowska,Iwona Solarska,Gertjan Driessen

doi:10.1007/s10875-016-0363-5

Ruud W J Meijers, Dennis Tielemans + Show 9 more

Open Access

https://doi.org/10.1007/s10875-016-0363-5

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Abstract

PurposeThe Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence.MethodsThe absolute numbers and frequencies of the different T cell subsets were determined in NBS patients from young age till adulthood and compared to age-matched healthy individuals (HI). In addition, we determined the expression of senescent T cell markers and the signal joint T cell receptor excision circles (sjTRECs) content.ResultsOur results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of αβ+ T cells, but normal γδ+ T cell numbers compared to HI. Concerning the αβ+ T cells, both CD4+ as well as CD8+ T cells were excessively reduced in numbers compared to aged-matched HI. In addition, NBS patients showed higher frequencies of the more differentiated T cells expressing the senescent cell marker CD57 and did not express co-stimulatory molecule CD28. These effects were already present in the youngest age group. Furthermore, NBS patients showed lower sjTREC content in their T cells possibly indicative of a lower thymic output.ConclusionsWe conclude that circulating T cells from NBS patients show signs of a senescent phenotype which is already present from young age on and which might explain their T cell immune deficiency.

Highlights

The Nijmegen breakage syndrome (NBS) is an inherited autosomal recessive disorder which belongs to the group of chromosome instability syndromes
By using TruCount tubes, absolute number of T, B, and natural killer (NK) cells were determined from peripheral blood of NBS patients and compared with aged-matched healthy individuals (HI) (Fig. 1)
In addition to the differentiation status of the T cells, our results demonstrated that the low number of naïve T cells might be the result of a lower thymic output of cells which is in line with the lower signal joint T cell receptor excision circles (sjTRECs) content for NBS patients

Summary

Introduction

The Nijmegen breakage syndrome (NBS) is an inherited autosomal recessive disorder which belongs to the group of chromosome instability syndromes. NBS patients have a mutation in the NBN gene (previously NBS1) located on chromosome 8q21. By combining together with MRE11 and RAD50 in the socalled MRN complex, NBN is involved in the repair of DNA double-strand breaks (DSBs) [2, 5]. Such DSBs arise from ionizing radiation, oxidizing agents, and occur in a physiological context during DNA replication, meiotic recombination, and V(D)J and class switch recombination [6]. The MRN complex acts as a marker of DNA breaks and is likely to be

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