Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence
J Clin Immunol
Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence
Ruud W. J. Meijers 0 1 2 3
Katarzyna Dzierzanowska-Fangrat 0 1 2 3
Magdalena Zborowska 0 1 2 3
Iwona Solarska 0 1 2 3
Dennis Tielemans 0 1 2 3
Bob A. C. van Turnhout 0 1 2 3
Gertjan Driessen 0 1 2 3
Mirjam van der Burg 0 1 2 3
Jacques J. M. van Dongen 0 1 2 3
Krystyna H. Chrzanowska 0 1 2 3
Anton W. Langerak 0 1 2 3
0 Department of Medical Genetics, The Children's Memorial Health Institute , Warsaw , Poland
1 Ruud W. J. Meijers
2 Department of Clinical Microbiology and Immunology, The Children's Memorial Health Institute , Warsaw , Poland
3 Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center Rotterdam , Wytemaweg 80, 3015 CN Rotterdam , The Netherlands
Purpose The 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. Methods The 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. Results Our results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of ??+ T cells, but normal ??+ T cell numbers compared to HI. Concerning the ??+ T cells, both CD4+ as well as CD8+ T cells were excessively reduced in numbers compared to agedmatched 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. Conclusions We 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.
T cells; NBS; senescence; CD28null; sjTREC
Introduction
The Nijmegen breakage syndrome (NBS) is an inherited
autosomal recessive disorder which belongs to the group of
chromosome instability syndromes. Characteristic for the
disease is the facial appearance of patients in combination with
microcephaly, growth retardation, an increased risk for
malignancies, and immunodeficiency [
1?3
]. NBS patients have a
mutation in the NBN gene (previously NBS1) located on
chromosome 8q21. Over 90% of the patients contain a
homozygous 5 nucleotide deletion (c.657del5) presumed to be of
Slavic origin (founder effect), which causes premature
termination at codon 219 [
4
].
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, but also 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
involved in both the homologous recombination (HR) and
non-homologous end joining (NHEJ) pathways [
7
]. It is
activated in response to DSBs, keeping the two DNA ends in
close proximity [
8
]. Scanning force microscopy confirmed
that juxtaposition of DNA ends indeed occurs through MRN
interactions [
9, 10
]. The MRN complex has been shown to
accumulate in large nuclear foci within minutes after DSB
formation [11]. Collectively, this suggests that the MRN
complex?probably in conjunction with other proteins?is
involved in tethering the DNA ends to allow DNA repair
proteins to complete their actions [
12
].
Another function of the MRN complex is to activate ATM,
a crucial mediator of the cellular response to DNA damage.
MRN recruits ATM to DNA breaks, which results in
dissociation of the ATM dimer enabling ATM to become activated
[
13
]. ATM phosphorylates many targets, including H2AX,
involved in the regulation of cellular checkpoint response
and DNA damage repair [
14
]. Phosphorylation of H2AX
results in recruitment and retention of cell-cycle checkpoint
proteins and DNA repair proteins. This allows to stop the
cellcycle and to initiate repair of DSBs [
14
]. Finally, the MRN
complex plays a role in maintenance of chromosomal integrity
in the cell [
15
].
Immune deficiency is a serious problem for NBS patients.
Both defects in the development of lymphocytes but also in
the lymphocytic function ha (...truncated)