Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations

Fuchizawa, Tatsuya; Adachi, Yuichi; Ito, Yasunori; Higashiyama, Hiroyuki; Kanegane, Hirokazu; Futatani, Takeshi; Kobayashi, Ichiro; Kamachi, Yusuke; Sakamoto, Tatsuo; Tsuge, Ikuya; Tanaka, Hiroshi; Banham, Alison H.; Ochs, Hans D.; Miyawaki, Toshio

doi:10.1016/j.clim.2007.08.004

Cited by 49 publications

(33 citation statements)

References 36 publications

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“…Our results demonstrating increased proportions of FOXP3 ϩ T cells in the circulation as soon as 3-5 days after birth confirm and extend previous results showing in a smaller, cross-sectional study increased expression of FOXP3 in CD4 ϩ T cells between birth and 4 -14 days of age (29). Together, these results indicate a very rapid recruitment of FOXP3-expressing T cells to the blood soon after birth or, alternatively, an up-regulation of FOXP3 in the circulating CD4 ϩ T cells, and that the first days in life appear to provide the window during which this cell subset is most dynamically affected.…”

Section: Discussionsupporting

confidence: 82%

Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4+CD25high Regulatory T Cells

Grindebacke

Stenstad

Quiding‐Järbrink

et al. 2009

The Journal of Immunology

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Migration of CD4+CD25+FOXP3+ regulatory T cells (Treg) is important for suppressing immune responses in different tissues. Previous studies show that the majority of Treg at birth express gut homing receptor α4β7 and that only few express CCR4, while the reverse pattern is found in adults. The age at which homing receptor switch occurs in vivo is not known. In this study, we show, in a prospective study of human infants from birth to 3 years of age, that homing receptor switch from α4β7 to CCR4 commences between 1 1/2 and 3 years of age and that Treg at that age also had started their switch to a memory phenotype. The majority of naive Treg express α4β7 in infants but not in adults, while the majority of memory Treg express CCR4 both infants and adults. The homing receptor expression on Treg corresponds to their actual migration properties, because Treg from cord blood migrate foremost toward the gut-associated chemokine CCL25. CD4+FOXP3+ T cell numbers increase rapidly in the circulation during the first days of life indicating conversion to suppressive Treg from CD25high Treg precursors. These findings suggest that the gut is the primary site of Treg stimulation to exogenous Ags during the first 18 mo of life and that homing receptor switch toward a more extra-intestinal phenotype occurs thereafter.

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Section: Discussionsupporting

confidence: 82%

Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4+CD25high Regulatory T Cells

Grindebacke

Stenstad

Quiding‐Järbrink

et al. 2009

The Journal of Immunology

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“…Although Wildin et al reported that the same mutation of the FOXP3 gene was causative of IPEX syndrome [7], we also carried out flow cytometric analysis to examine the effect of this mutation on the FOXP3 protein level. We found that the patient's percentage of CD4 + CD25 + FOXP3 + T cells (0.86%) was much lower than that of other family members and a normal control [normal range of 4-6-year olds, n=12, 5.33±1.68% (3.39-8.60%)] [8] (Fig. 3), indicating that this mutation had resulted in the aberrant expression of FOXP3 protein.…”

Section: Resultsmentioning

confidence: 62%

Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

et al. 2009

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Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748-750delAAG, p.250K.del) and a paucity of CD4(+) CD25(+) FOXP3(+) T cells. The boy's condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS.

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“…Only one of the mutations had previously been reported (c.227delT; p.Leu76GlnfsX53). It introduces a frameshift and generates a premature stop codon (17,18). The inheritance within families of the mutations is in keeping with an X-linked inheritance as shown in Fig.…”

Section: Molecular Geneticsmentioning

confidence: 87%

Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes

et al. 2009

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OBJECTIVE -Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).RESEARCH DESIGN AND METHODS -The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes.RESULTS -We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P ϭ 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n ϭ 2) or nephrotic syndrome (n ϭ 1) and survival to 12-15 years.CONCLUSIONS -FOXP3 mutations result in ϳ4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.

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Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations

Cited by 49 publications

References 36 publications

Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4+CD25high Regulatory T Cells

Dynamic Development of Homing Receptor Expression and Memory Cell Differentiation of Infant CD4+CD25high Regulatory T Cells

Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes

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