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

  1. Ezio Bonifacio3
  1. 1San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy
  2. 2Institute of Diabetes Research, Helmholtz Center Munich, Neuherberg, Germany
  3. 3Center for Regenerative Therapies Dresden-DFG Research Center and Cluster of Excellence, Technische Universität Dresden, Dresden, Germany
  1. Corresponding author: Paolo Monti, paolo.monti{at}hsr.it.

Abstract

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.

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  1. Diabetes vol. 62 no. 7 2500-2508
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