title: Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes.
abstract: BACKGROUND
  Reduced risk for type 1 diabetes (T1D) has been reported in the offspring of mothers with T1D 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 FOXP3 expressing regulatory T cells in cord blood (CB) of infants born to mothers with or without T1D.
  
  
  METHODS
  Cord blood mononuclear cells (CBMCs) from 20 infants with maternal T1D and from 20 infants with an unaffected mother were analyzed for the numbers of CD4+CD25+FOXP3+ cells ex vivo and after in vitro stimulation with human insulin by flow cytometry. The mRNA expression of FOXP3, NFATc2, STIM1, interleukin (IL)-10, and transforming growth factor (TGF)-β was measured by real-time reverse transcription polymerase chain reaction.
  
  
  RESULTS
  The percentage of FOXP3+ cells in CD4+CD25(high)  cells was higher in the CB of the infants with maternal T1D when compared with the infants of unaffected mothers (p = 0.023). After in vitro insulin stimulation an increase in the percentage of FOXP3+ cells in CD4+CD25(high)  cells (p = 0.0002) as well as upregulation of FOXP3, NFATc2, STIM1, IL-10, and TGF-β transcripts in CBMCs (p < 0.013 for all; Wilcoxon test) was observed only in the offspring of mothers with T1D, in whom the disease-related PTPN22 allele was associated with reduced STIM1 and NFATc2 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.
authors.affiliation: Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland. kristiina.luopajarvi@thl.fi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Luopajärvi
authors.forename: Janne K
authors.initials: JK
authors.lastname: Nieminen
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Hans K
authors.initials: HK
authors.lastname: Akerblom
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D015704:CD4 Antigens / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000097:blood*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood*; D008297:Male; D009035:Mothers; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit