title: Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.
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.
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, U.K. National Institute of Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London, London, U.K. timothy.tree@kcl.ac.uk jennie.yang@kcl.ac.uk.
authors.forename: Jennie H M
authors.initials: JH
authors.lastname: Yang
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, U.K. National Institute of Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London, London, U.K.
authors.forename: James L
authors.initials: JL
authors.lastname: Reading
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cooper
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Pamela
authors.initials: P
authors.lastname: Clarke
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.affiliation: BD Biosciences, Cell Analysis, San Diego, CA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Boyce
authors.affiliation: BD Biosciences, Cell Analysis, San Diego, CA.
authors.forename: Guo-Jian
authors.initials: GJ
authors.lastname: Gao
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, U.K. National Institute of Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and King's College London, London, U.K. timothy.tree@kcl.ac.uk jennie.yang@kcl.ac.uk.
authors.forename: Timothy I M
authors.initials: TI
authors.lastname: Tree
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000502:physiology*
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2