title: The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies.
abstract: NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naïve CD8+ T cells into highly activated, cytotoxic CD8+NKG2Dhigh T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. CD8+NKG2Dhigh T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68+ macrophages as well as CD4+ T cells, and CD8+NKG2D+ cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Ali Maisam
authors.initials: AM
authors.lastname: Afzali
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Glumm
authors.affiliation: Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Preuße
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D032446:Myoblasts / Q000378:metabolism; D009220:Myositis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K
keywords: IL-15; NKG2D; Pathology Section; T cell activation; idiopathic inflammatory myopathies; polymyositis