Concentration and Activity of the Soluble Form of the Interleukin-7 Receptor α in Type 1 Diabetes Identifies an Interplay Between Hyperglycemia and Immune Function
- 1San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy
- 2Institute of Diabetes Research, Helmholtz Center Munich, Neuherberg, Germany
- 3Center for Regenerative Therapies Dresden-DFG Research Center and Cluster of Excellence, Technische Universität Dresden, Dresden, Germany
- Corresponding author: Paolo Monti, .
Soluble interleukin-7 (IL-7) receptor α (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (T1D; n = 390) as compared with concentrations in age-matched islet autoantibody–negative first-degree relatives of patients (n = 392; P = 0.00001). sCD127 concentration in patients was influenced by islet autoantibody status (P = 0.003) and genotype of the rs6897932 single nucleotide polymorphism within the IL-7RA gene (P = 0.006). Release of sCD127 in vitro was strongly upregulated by activation of T lymphocytes and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7–mediated T-cell proliferation, suggesting a regulatory feedback mechanism on T-cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of T1D suggested that physiological regulation of IL-7–mediated T-cell survival and expansion by sCD127 may be compromised in T1D. The findings indicate that genetic, immunologic, and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in T1D and identify a novel hyperglycemia-mediated interference of immune regulatory networks.
- Received December 11, 2012.
- Accepted February 25, 2013.
- © 2013 by the American Diabetes Association.
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