title: 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.
abstract: Low-dose interleukin-2 (IL-2) inhibited unwanted immune responses in several clinical settings and is currently being tested in patients with type 1 diabetes (T1D). Low-dose IL-2 selectively targets regulatory T cells (Tregs), but the mechanisms underlying this selectivity are poorly understood. We show that IL-2-dependent STAT5 activation in Tregs from healthy individuals and patients with T1D occurred at an ∼10-fold lower concentration of IL-2 than that required by T memory (TM) cells or by in vitro-activated T cells. This selective Treg responsiveness is explained by their higher expression of IL-2 receptor subunit α (IL-2Rα) and γ chain and also endogenous serine/threonine phosphatase protein phosphates 1 and/or 2A activity. Genome-wide profiling identified an IL-2-dependent transcriptome in human Tregs. Quantitative assessment of selected targets indicated that most were optimally activated by a 100-fold lower concentration of IL-2 in Tregs versus CD4(+) TM cells. Two such targets were selectively increased in Tregs from T1D patients undergoing low-dose IL-2 therapy. Thus, human Tregs possess an IL-2-dependent transcriptional amplification mechanism that widens their selective responses to low IL-2. Our findings support a model where low-dose IL-2 selectively activates Tregs to broadly induce their IL-2/IL-2R gene program and provide a molecular underpinning for low-dose IL-2 therapy to enhance Tregs for immune tolerance in T1D.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Aixin
authors.initials: A
authors.lastname: Yu
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Isaac
authors.initials: I
authors.lastname: Snowhite
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vendrame
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France Sorbonne Université, Université Pierre et Marie Curie Univ Paris 06, Unité Mixte de Recherche (UMR)-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France INSERM, UMR-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), Paris, France Sorbonne Université, Université Pierre et Marie Curie Univ Paris 06, Unité Mixte de Recherche (UMR)-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France INSERM, UMR-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL tmalek@med.miami.edu.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Malek
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D050799:STAT5 Transcription Factor