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

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.

[1]  D. Klatzmann,et al.  Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. , 2015, Journal of autoimmunity.

[2]  J. Todd,et al.  IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients , 2015, Diabetologia.

[3]  D. Klatzmann,et al.  Selective IL-2 Responsiveness of Regulatory T Cells Through Multiple Intrinsic Mechanisms Supports the Use of Low-Dose IL-2 Therapy in Type 1 Diabetes , 2015, Diabetes.

[4]  M. Ono,et al.  Follicular helper T cell signature in type 1 diabetes. , 2015, The Journal of clinical investigation.

[5]  P. Bingley,et al.  Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes , 2014, Diabetes.

[6]  J. Todd,et al.  Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes , 2014, Clinical and experimental immunology.

[7]  Thomas E. Hughes,et al.  Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[8]  P. Bahadoran,et al.  Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. , 2014, JAMA dermatology.

[9]  J. Todd,et al.  Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial , 2014, BMJ Open.

[10]  J. Melenhorst,et al.  Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity , 2014, Clinical Cancer Research.

[11]  Elizabeth Whalen,et al.  Multiple Autoimmune-Associated Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 1 Diabetic and Multiple Sclerosis Patients , 2013, PloS one.

[12]  D. Klatzmann,et al.  Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. , 2013, The lancet. Diabetes & endocrinology.

[13]  Tao Yang,et al.  Inhibition of Increased Circulating Tfh Cell by Anti-CD20 Monoclonal Antibody in Patients with Type 1 Diabetes , 2013, PloS one.

[14]  J. Ritz,et al.  Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease , 2013, Science Translational Medicine.

[15]  Calliope A. Dendrou,et al.  Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors , 2013, The Journal of Immunology.

[16]  J. Bluestone,et al.  Rapamycin/IL-2 Combination Therapy in Patients With Type 1 Diabetes Augments Tregs yet Transiently Impairs β-Cell Function , 2012, Diabetes.

[17]  M. Kopf,et al.  IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. , 2012, Blood.

[18]  Linda S. Wicker,et al.  Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function , 2012, The Journal of Immunology.

[19]  S. Glišić,et al.  Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis , 2012, PloS one.

[20]  F. Carrat,et al.  Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. , 2011, The New England journal of medicine.

[21]  S. Quataert,et al.  Uncoupling of Proliferation and Cytokines From Suppression Within the CD4+CD25+Foxp3+ T–Cell Compartment in the 1st Year of Human Type 1 Diabetes , 2011, Diabetes.

[22]  J. Bluestone,et al.  IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells , 2010, The Journal of experimental medicine.

[23]  K. Cerosaletti,et al.  An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells , 2010, Genes and Immunity.

[24]  Sarah E. Jackson,et al.  Different Proliferative Potential and Migratory Characteristics of Human CD4+ Regulatory T Cells That Express either CD45RA or CD45RO , 2010, The Journal of Immunology.

[25]  K. Cerosaletti,et al.  Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects , 2009, Diabetes.

[26]  Matthew Hardy,et al.  Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource , 2009, Nature Genetics.

[27]  Purushottam W. Laud,et al.  Apoptosis of CD4+CD25high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation , 2009, PloS one.

[28]  T. Nomura,et al.  Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. , 2009, Immunity.

[29]  Linjiang Zhu,et al.  A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. , 2009, Immunity.

[30]  M. Peakman,et al.  Increased resistance to CD4+CD25hi regulatory T cell‐mediated suppression in patients with type 1 diabetes , 2008, Clinical and experimental immunology.

[31]  J. Buckner,et al.  The Effector T Cells of Diabetic Subjects Are Resistant to Regulation via CD4+FOXP3+ Regulatory T Cells1 , 2008, The Journal of Immunology.

[32]  J. Bluestone,et al.  Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. , 2008, Immunity.

[33]  M. Battaglia,et al.  STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells. , 2008, International immunology.

[34]  Matthew A Burchill,et al.  Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. , 2007, Immunology letters.

[35]  R. A. Bailey,et al.  Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes , 2007, Nature Genetics.

[36]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[37]  A. Rudensky,et al.  Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3 , 2007, Nature Immunology.

[38]  W. Hagopian,et al.  At-Risk and Recent-Onset Type 1 Diabetic Subjects Have Increased Apoptosis in the CD4+CD25+high T-Cell Fraction , 2007, PloS one.

[39]  Garry P Nolan,et al.  Fluorescent cell barcoding in flow cytometry allows high-throughput drug screening and signaling profiling , 2006, Nature Methods.

[40]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[41]  M. Atkinson,et al.  Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. , 2005, Diabetes.

[42]  T. Malek,et al.  Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period , 2005, The Journal of experimental medicine.

[43]  Shimon Sakaguchi,et al.  Homeostatic maintenance of natural Foxp3 + CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization , 2005, The Journal of experimental medicine.

[44]  T. Malek,et al.  Tolerance, not immunity, crucially depends on IL-2 , 2004, Nature Reviews Immunology.

[45]  Helen Schuilenburg,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[46]  M. Peakman,et al.  Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. , 2005, Diabetes.