title: Dominant TNFα and impaired IL-2 cytokine profiles of CD4+T cells from children with type-1 diabetes.
abstract: Aberrantly activated CD4+T memory cells play a central role in the development of type-1-diabetes. Interleukin-7 promotes generation of autoimmune memory T cells and increased Interleukin-7 availability is associated with type-1-diabetes susceptibility. T-cell-mediated immune pathology at onset of type-1-diabetes is well defined, but characteristics of long-term symptomatic disease stages remain largely elusive. In the present study, memory CD4+T-cell activation and cytokine expression as well as sensitivity to Interleukin-7 in vitro were compared between patients with type-1-diabetes at clinical onset (n=25), long-term symptomatic disease (median duration 4.5 years, n=19) and matched healthy controls (n=21). T-cell responses of type-1-diabetes patients were characterized by higher frequencies of cytokine and activation marker expressing CD4+memory T cells as compared to healthy controls. Notably, correction for individual cytokine expression levels revealed qualitative differences of cytokine profiles characterized by significantly increased TNFα and decreased IL-2-expressing T-cell proportions in long-term type-1-diabetes patients. IL-7-mediated T-cell co-stimulation induced quantitative and qualitative cytokine expression differences highly similar to type-1-diabetes-specific profiles. In addition, CD4+memory T cells from children with long-term type-1-diabetes were more sensitive to in vitro IL-7 co-stimulation. Global transcriptome analysis revealed IL-7 induced expression differences of CD4+T cells, including increased IL-2R expression and effects on subsequent T-cell receptor activation. We conclude that long-term symptomatic type-1-diabetes patients differed in memory T-cell cytokine profiles and Interleukin-7 co-stimulation. Regulation of IL-2 expression and sensitivity are affected with possible consequences for disease course and severity at long-term type-1-diabetes stages.
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.|German Center for Diabetes Research (DZD), Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Seyfarth
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Förtsch
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ahlert
authors.affiliation: Department of Pediatric Hematology, Onocology and Clinical Immunology; University Children's Hospital, Duesseldorf, Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Laws
authors.affiliation: Division of Endocrinology and Diabetes, RWTH Aachen University, German Center for Diabetes Research (DZD), Aachen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Karges
authors.affiliation: Biological and Medical Research Center (BMFZ), Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Deenen
authors.affiliation: Biological and Medical Research Center (BMFZ), Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.|German Center for Diabetes Research (DZD), Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobsen
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015851:Interleukin-7 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma