CD4+FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome

Abstract

ObjectiveWe investigated whether the frequency, phenotype, and suppressive function of CD4+FOXP3+ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls.Design and MethodsPeripheral blood mononuclear cells from young TS patients (n = 24, 17.4–35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (–) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4+CD25bright were co-cultured with autologous CD4+CD25− target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function.ResultsDespite a lower frequency of CD4+ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+CD25− T cells was significantly impaired in the TS (–) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (–) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group.ConclusionsThe Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.

Autoimmune Thyroid Disease in Specific Genetic Syndromes in Childhood and Adolescence

“…The X chromosome is known to contain many immune-related genes ( 36 , 37 ), one of them being FOXP3 (forkhead box P3). FOXP3, a member of the forkhead family of transcription factors is an essential transcriptional regulator for the development and suppressive function of regulatory T cells (Tregs), a subset of CD4+ lymphocytes ( 35 , 38 ). Of note, Zinn et al have mapped a possible locus for autoimmune thyroid disease in TS to a critical region of X chromosome, Xp11.2-p22.1, which also contains FOXP3 gene ( 38 , 39 ).…”

“…FOXP3, a member of the forkhead family of transcription factors is an essential transcriptional regulator for the development and suppressive function of regulatory T cells (Tregs), a subset of CD4+ lymphocytes ( 35 , 38 ). Of note, Zinn et al have mapped a possible locus for autoimmune thyroid disease in TS to a critical region of X chromosome, Xp11.2-p22.1, which also contains FOXP3 gene ( 38 , 39 ). Mutations in the FOXP3 gene cause a rare disorder inherited in males, known as IPEX syndrome (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked) that can be also characterized by ATD ( 38 ).…”

Autoimmunity Predisposition in Girls With Turner Syndrome

“…The findings in TS patients are inconclusive. Lee et al demonstrated that although TS patients have a relatively higher number of Treg cells among CD4+ lymphocytes than healthy controls, these cells cannot efficiently suppress an autoimmune reaction (16). The latest study by Gawlik et al showed that the percentage of Treg cells in girls with TS and coexisting autoimmunity was lower than in the healthy controls and in TS girls without autoimmune diseases (17).…”

A child with Klinefelter syndrome and both IgE‐mediated food allergy and low proportion of naive Treg

“…Investigations of Treg measures have been performed in Turners syndrome, a 45,X karyotype; however no changes in frequency were observed. 9 KS is associated with variable inactivation of the surplus X chromosome(s), 1 and differential expression of a number of X-chromosomal genes has been reported. 10 Our data support a link between the atypical copy number of FOXP3 in KS, a decrease in nTreg, and an increased risk of allergic disease.…”

“…There are currently no reports of the frequency of nTreg in KS. Investigations of Treg measures have been performed in Turners syndrome, a 45,X karyotype; however no changes in frequency were observed . KS is associated with variable inactivation of the surplus X chromosome(s), and differential expression of a number of X‐chromosomal genes has been reported .…”