title: Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis.
abstract: Expansion of circulating CD28- T-cells reminiscent of effector memory T-cells (T(EM)) has been reported in Wegener's granulomatosis (WG) recently. To investigate the role of T(EM) in WG, we analyzed the expression of the activating NK-receptor NKG2D and its ligand MIC on circulating T(EM) and in granulomatous lesions, respectively. NKG2D was anomalously expressed and preferentially detected on circulating CD4+CD28- T(EM) in WG. Compared to healthy controls, T(EM) display a more activated phenotype potentially favoring unbalanced proinflammatory responses in WG. Cluster-like formations of "Wegener's autoantigen" PR3 were surrounded by NKG2D+ and NKG2D-ligand MIC+ cells in WG-granulomata, but not in disease controls. Further, IL-15 - known to drive T(EM) differentiation and proliferation--was also expressed in WG-granulomata. Thus, through acquisition of NK-like "innate" properties, IL-15 stimulated NKG2D+ T(EM) could interact with MIC+ cells within WG-granulomata, thereby sustaining inflammation and autoimmunity and promoting self-perpetuating pathology in WG.
authors.affiliation: University of Lübeck, Department of Rheumatology, Vasculitiscenter & Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Dorin
authors.initials: D
authors.lastname: Capraru
authors.forename: Antje
authors.initials: A
authors.lastname: Müller
authors.forename: Elena
authors.initials: E
authors.lastname: Csernok
authors.forename: Wolfgang L
authors.initials: WL
authors.lastname: Gross
authors.forename: Konstanze
authors.initials: K
authors.lastname: Holl-Ulrich
authors.forename: John
authors.initials: J
authors.lastname: Northfield
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Karen
authors.initials: K
authors.lastname: Herlyn
authors.forename: Julia
authors.initials: J
authors.lastname: Holle
authors.forename: Stefan
authors.initials: S
authors.lastname: Gottschlich
authors.forename: Jan
authors.initials: J
authors.lastname: Voswinkel
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Ursula
authors.initials: U
authors.lastname: Fagin
authors.forename: Wolfram J
authors.initials: WJ
authors.lastname: Jabs
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
mesh_terms: D001706:Biopsy; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D053146:Myeloblastin / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D055607:Receptors, Natural Killer Cell
chemical_list: D018106:CD28 Antigens; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423230:ULBP2 protein, human; D053146:Myeloblastin