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



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Yang, Jennie HM 
Cutler, Antony J 
Ferreira, Ricardo C 
Reading, James L 
Cooper, Nicholas J 


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.



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

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American Diabetes Association
Wellcome Trust (089989/Z/09/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (091157/Z/10/B)
Wellcome Trust (061858/Z/00/E)
This work was supported by the JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the Wellcome Trust (WT061858/091157) and the NIHR Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).