Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes

Jennie H M Yang, Antony J Cutler, Ricardo C Ferreira, James L Reading, Nicholas J Cooper, Chris Wallace, Pamela Clarke, Deborah J Smyth, Christopher S Boyce, Guo-Jian Gao, John A Todd, Linda S Wicker, Timothy I M Tree

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.

Original languageEnglish
Pages (from-to)3891-902
Number of pages12
JournalDiabetes
Volume64
Issue number11
Early online date29 Jul 2015
DOIs
Publication statusPublished - 30 Nov 2015

Keywords

  • Diabetes Mellitus, Type 1
  • Genotype
  • Humans
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Signal Transduction
  • T-Lymphocytes, Regulatory

Fingerprint

Dive into the research topics of 'Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes'. Together they form a unique fingerprint.

Cite this