title: IL-17 immunity in human type 1 diabetes.
abstract: Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-gamma-secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17-positive T cells appeared to be CD4(+) cells expressing TCR-alphabeta and CCR6, and a subpopulation showed coproduction of IFN-gamma. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.
authors.affiliation: Immune Response Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jarno
authors.initials: J
authors.lastname: Honkanen
authors.forename: Janne K
authors.initials: JK
authors.lastname: Nieminen
authors.forename: Ru
authors.initials: R
authors.lastname: Gao
authors.forename: Kristiina
authors.initials: K
authors.lastname: Luopajarvi
authors.forename: Harri M
authors.initials: HM
authors.lastname: Salo
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D000293:Adolescent; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000009:adverse effects / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D000097043:Interleukin-22; C418974:FOXP3 protein, human; C539900:RORC protein, human