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- Title
Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.
- Authors
Yang, Jennie H. M.; Cutler, Antony J.; Ferreira, Ricardo C.; Reading, James L.; Cooper, Nicholas J.; Wallace, Chris; Clarke, Pamela; Smyth, Deborah J.; Boyce, Christopher S.; Guo-Jian Gao; Todd, John A.; Wicker, Linda S.; Tree, Timothy I. M.; Gao, Guo-Jian
- 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.
- Subjects
INTERLEUKIN-2; T cells; TYPE 1 diabetes; HOMEOSTASIS; GENETIC polymorphisms; IMMUNOTHERAPY; PHOSPHORYLATION; CELLULAR signal transduction; ESTERASES; RESEARCH funding; GENOTYPES; PHYSIOLOGY
- Publication
Diabetes, 2015, Vol 64, Issue 11, p3891
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-0516