Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects

S. Alice Long, Karen Cerosaletti, Paul L. Bollyky, Megan Tatum, Heather Shilling, Sheng Zhang, Zhong-Yin Zhang, Catherine Pihoker, Srinath Sanda, Carla Greenbaum, Jane H. Buckner

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)407-415
Number of pages9
JournalDiabetes
Volume59
Issue number2
DOIs
StatePublished - Feb 2010

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Interleukins
Regulatory T-Lymphocytes
Interleukin-2
Maintenance
Type 1 Diabetes Mellitus
Interleukin-7
T-Lymphocytes
Flow Cytometry
STAT5 Transcription Factor
Interleukin-15
Cytokine Receptors
Protein Tyrosine Phosphatases
Interleukin-2 Receptors
Autoimmunity
Anti-Idiotypic Antibodies
Research Design
Biomarkers
Western Blotting
Phosphorylation
Population

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Long, S. A., Cerosaletti, K., Bollyky, P. L., Tatum, M., Shilling, H., Zhang, S., ... Buckner, J. H. (2010). Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. Diabetes, 59(2), 407-415. https://doi.org/10.2337/db09-0694

Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. / Long, S. Alice; Cerosaletti, Karen; Bollyky, Paul L.; Tatum, Megan; Shilling, Heather; Zhang, Sheng; Zhang, Zhong-Yin; Pihoker, Catherine; Sanda, Srinath; Greenbaum, Carla; Buckner, Jane H.

In: Diabetes, Vol. 59, No. 2, 02.2010, p. 407-415.

Research output: Contribution to journalArticle

Long, SA, Cerosaletti, K, Bollyky, PL, Tatum, M, Shilling, H, Zhang, S, Zhang, Z-Y, Pihoker, C, Sanda, S, Greenbaum, C & Buckner, JH 2010, 'Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects', Diabetes, vol. 59, no. 2, pp. 407-415. https://doi.org/10.2337/db09-0694
Long, S. Alice ; Cerosaletti, Karen ; Bollyky, Paul L. ; Tatum, Megan ; Shilling, Heather ; Zhang, Sheng ; Zhang, Zhong-Yin ; Pihoker, Catherine ; Sanda, Srinath ; Greenbaum, Carla ; Buckner, Jane H. / Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. In: Diabetes. 2010 ; Vol. 59, No. 2. pp. 407-415.
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abstract = "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.",
author = "Long, {S. Alice} and Karen Cerosaletti and Bollyky, {Paul L.} and Megan Tatum and Heather Shilling and Sheng Zhang and Zhong-Yin Zhang and Catherine Pihoker and Srinath Sanda and Carla Greenbaum and Buckner, {Jane H.}",
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T1 - Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects

AU - Long, S. Alice

AU - Cerosaletti, Karen

AU - Bollyky, Paul L.

AU - Tatum, Megan

AU - Shilling, Heather

AU - Zhang, Sheng

AU - Zhang, Zhong-Yin

AU - Pihoker, Catherine

AU - Sanda, Srinath

AU - Greenbaum, Carla

AU - Buckner, Jane H.

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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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