title: Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death.
abstract: OBJECTIVE
  CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells.
  
  
  METHODS
  Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat β-cells, and the rat insulinoma cell line INS-1E were examined.
  
  
  RESULTS
  A total of 27 patients (54%) showed IL-17 reactivity to one or more β-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1β/interferon (IFN)-γ-induced and tumor necrosis factor (TNF)-α/IFN-γ-induced apoptosis in human islets, rat β-cells, and INS-1E cells, in association with significant upregulation of β-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB.
  
  
  CONCLUSIONS
  Circulating IL-17(+) β-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to β-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target.
authors.affiliation: Department of Immunobiology, School of Medicine, King’s College London, London, UK.
authors.forename: Sefina
authors.initials: S
authors.lastname: Arif
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moore
authors.forename: Katherine
authors.initials: K
authors.lastname: Marks
authors.forename: Thomas
authors.initials: T
authors.lastname: Bouckenooghe
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Raquel
authors.initials: R
authors.lastname: Planas
authors.forename: Marta
authors.initials: M
authors.lastname: Vives-Pi
authors.forename: Jake
authors.initials: J
authors.lastname: Powrie
authors.forename: Timothy
authors.initials: T
authors.lastname: Tree
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Guo Cai
authors.initials: GC
authors.lastname: Huang
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pujol-Borrell
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D007340:Insulinoma / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D007378:Interleukins; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C508717:IL17A protein, human; C539900:RORC protein, human; C494079:STAT1 protein, human