1. Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes
- Author
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Yang, Jennie HM, Cutler, Antony J, Ferreira, Ricardo C, Reading, James L, Cooper, Nicholas J, Wallace, Chris, Clarke, Pamela, Smyth, Deborah J, Boyce, Christopher S, Gao, Guo-Jian, Todd, John A, Wicker, Linda S, Tree, Timothy IM, Wallace, Chris [0000-0001-9755-1703], and Apollo - University of Cambridge Repository
- Subjects
Protein Tyrosine Phosphatase, Non-Receptor Type 2 ,Diabetes Mellitus, Type 1 ,Genotype ,Interleukin-2 Receptor alpha Subunit ,Humans ,Interleukin-2 ,Polymorphism, Single Nucleotide ,T-Lymphocytes, Regulatory ,Signal Transduction - 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.
- Published
- 2015