title: Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+cells.
abstract: T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3loTregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: A K
authors.initials: AK
authors.lastname: Marwaha
authors.affiliation: Department of Pediatrics, University of British Columbia and Endocrine and Diabetes Unit, British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Panagiotopoulos
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Biggs
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Staiger
authors.affiliation: Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada.
authors.forename: K L
authors.initials: KL
authors.lastname: Del Bel
authors.affiliation: Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada.
authors.forename: A F
authors.initials: AF
authors.lastname: Hirschfeld
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Priatel
authors.affiliation: Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Turvey
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.|Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.|Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Doha, Qatar.
authors.forename: R
authors.initials: R
authors.lastname: Tan
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007108:Immune Tolerance; D020381:Interleukin-17 / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D011379:Prognosis; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508717:IL17A protein, human; D020381:Interleukin-17; D007376:Interleukin-2