Poor in Vitro Induction of FOXP3 and ICOS in Type 1 Cytokine Environment Activated T-cells From Children With Type 1 Diabetes

Diabetes Metab Res Rev. Nov-Dec 2008;24(8):635-41. doi: 10.1002/dmrr.904.


Background: Type 1 diabetes (T1D) is characterised by loss of tolerance to beta-cell antigens, and the insulin-producing beta-cells in the pancreatic islets are destroyed by the host's own immune system. Immunological risk factors associated with T1D are related to the defects in the polarization of T-cells and in the function of regulatory T (Treg)-cells. We set out to study whether an impaired induction of regulatory mechanisms during the generation of T-cell responses upon stimulation is associated with T1D.

Methods: Naive T-cells were isolated from 18 children with recent T1D (0-14days from diagnosis; mean age 9.3 years), 11 children who had had T1D for at least 1 year (mean age 10.6) and 14 non-diabetic children (mean age 8.1). CD45RA+ T-cells were stimulated with PHA for 72 h in type 1 cytokine [interleukin (IL)-12 and anti-IL-4] or type 2 cytokine (IL-4 and anti-IL-12) environment. T-cell polarization and regulation related markers were analysed by quantitative reverse transcription polymerase chain reaction (QRT-PCR) (Th1 promoting T-bet, Th2 promoting GATA-3 and regulation related FOXP3, ICOS and NFATc2).

Results: Children with recently diagnosed T1D showed decreased induction of FOXP3, ICOS and NFATc2 in T-cells activated in type 1 cytokine milieu (p = 0.007, p = 0.001, and p = 0.02), whereas no differences between the diabetic and healthy children were seen in the up-regulation of activation markers, T-bet and GATA-3.

Conclusions: The poor induction of factors that mediate down-modulation of T-cell responses upon stimulation in type 1 cytokine environment may contribute to the development of autoreactive type 1 responses in T1D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation, T-Lymphocyte / genetics*
  • Child
  • Cytokines / physiology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics*
  • Humans
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-12 / immunology
  • Interleukin-4 / immunology
  • Lymphocyte Activation
  • NFATC Transcription Factors / genetics
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology*


  • Antigens, Differentiation, T-Lymphocyte
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • NFATC Transcription Factors
  • NFATC1 protein, human
  • RNA, Messenger
  • Interleukin-12
  • Interleukin-4