Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects

  1. S. Alice Long1,
  2. Karen Cerosaletti1,
  3. Paul L. Bollyky1,
  4. Megan Tatum1,
  5. Heather Shilling1,
  6. Sheng Zhang2,
  7. Zhong-Yin Zhang2,
  8. Catherine Pihoker3,
  9. Srinath Sanda1,
  10. Carla Greenbaum1 and
  11. Jane H. Buckner1
  1. 1Benaroya Research Institute at Virginia Mason, Seattle, Washington;
  2. 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana;
  3. 3Seattle Children's Hospital, Seattle, Washington.
  1. Corresponding author: Jane H. Buckner, jbuckner{at}


OBJECTIVE In humans, multiple genes in the interleukin (IL)-2/IL-2 receptor (IL-2R) pathway are associated with type 1 diabetes. However, no link between IL-2 responsiveness and CD4+CD25+FOXP3+ regulatory T-cells (Tregs) has been demonstrated in type 1 diabetic subjects despite the role of these IL-2–dependent cells in controlling autoimmunity. Here, we address whether altered IL-2 responsiveness impacts persistence of FOXP3 expression in Tregs of type 1 diabetic subjects.

RESEARCH DESIGN AND METHODS Persistence of Tregs was assessed by culturing sorted CD4+CD25hi natural Tregs with IL-2 and measuring FOXP3 expression over time by flow cytometry for control and type 1 diabetic populations. The effects of IL-2 on FOXP3 induction were assessed 48 h after activation of CD4+CD25 T-cells with anti-CD3 antibody. Cytokine receptor expression and signaling upon exposure to IL-2, IL-7, and IL-15 were determined by flow cytometry and Western blot analysis.

RESULTS Maintenance of FOXP3 expression in CD4+CD25+ Tregs of type 1 diabetic subjects was diminished in the presence of IL-2, but not IL-7. Impaired responsiveness was not linked to altered expression of the IL-2R complex. Instead, IL-2R signaling was reduced in Tregs and total CD4+ T-cells of type 1 diabetic subjects. In some individuals, decreased signal transducer and activator of transcription 5 phosphorylation correlated with significantly higher expression of protein tyrosine phosphatase N2, a negative regulator of IL-2R signaling.

CONCLUSIONS Aberrant IL-2R signaling in CD4+ T-cells of type 1 diabetic subjects contributes to decreased persistence of FOXP3 expression that may impact establishment of tolerance. These findings suggest novel targets for treatment of type 1 diabetes within the IL-2R pathway and suggest that an altered IL-2R signaling signature may be a biomarker for type 1 diabetes.


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    • Received May 8, 2009.
    • Accepted October 16, 2009.
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  1. Diabetes vol. 59 no. 2 407-415
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