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Expansion of CD 4+ CD 25+ FOXP 3+ regulatory T cells in infants of mothers with type 1 diabetes
Author(s) -
Luopajärvi Kristiina,
Nieminen Janne K,
Ilonen Jorma,
Åkerblom Hans K,
Knip Mikael,
Vaarala Outi
Publication year - 2012
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/j.1399-5448.2012.00852.x
Subject(s) - foxp3 , medicine , il 2 receptor , endocrinology , offspring , type 1 diabetes , insulin , peripheral blood mononuclear cell , cord blood , immunology , diabetes mellitus , biology , pregnancy , in vitro , t cell , immune system , biochemistry , genetics
Background Reduced risk for type 1 diabetes ( T 1 D ) has been reported in the offspring of mothers with T 1 D when compared with children of affected fathers. Objective To evaluate the hypothesis that exposure of the offspring to maternal insulin therapy induces regulatory mechanisms in utero , we compared the FOXP 3 expressing regulatory T cells in cord blood ( CB ) of infants born to mothers with or without T 1 D . Subjects and Methods Cord blood mononuclear cells ( CBMCs ) from 20 infants with maternal T 1 D and from 20 infants with an unaffected mother were analyzed for the numbers of CD 4+ CD 25+ FOXP 3+ cells ex vivo and after in vitro stimulation with human insulin by flow cytometry. The mRNA expression of FOXP 3, NFATc 2, STIM 1, interleukin ( IL )‐10, and transforming growth factor ( TGF )‐β was measured by real‐time reverse transcription polymerase chain reaction. Results The percentage of FOXP 3+ cells in CD 4+ CD 25 high cells was higher in the CB of the infants with maternal T 1 D when compared with the infants of unaffected mothers (p = 0.023). After in vitro insulin stimulation an increase in the percentage of FOXP 3+ cells in CD 4+ CD 25 high cells (p = 0.0002) as well as upregulation of FOXP 3, NFATc 2, STIM 1, IL ‐10, and TGF ‐β transcripts in CBMCs (p < 0.013 for all; Wilcoxon test) was observed only in the offspring of mothers with T 1 D , in whom the disease‐related PTPN 22 allele was associated with reduced STIM 1 and NFATc 2 response in insulin‐stimulated CBMCs (p = 0.007 and p = 0.014). Conclusions We suggest that maternal insulin treatment induces expansion of regulatory T cells in the fetus, which might contribute to the lower risk of diabetes in children with maternal vs. paternal diabetes.