Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes

Pediatr Diabetes. 2012 Aug;13(5):400-7. doi: 10.1111/j.1399-5448.2012.00852.x. Epub 2012 Feb 15.

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.

Subjects and 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4 Antigens / blood*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Fetal Blood / immunology
  • Forkhead Transcription Factors / blood*
  • Humans
  • Infant
  • Infant, Newborn
  • Insulin / therapeutic use
  • Interleukin-2 Receptor alpha Subunit / blood*
  • Male
  • Mothers
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Insulin
  • Interleukin-2 Receptor alpha Subunit