Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis.
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.
Capraru
Dorin
D
University of Lübeck, Department of Rheumatology, Vasculitiscenter & Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Müller
Antje
A
Csernok
Elena
E
Gross
Wolfgang L
WL
Holl-Ulrich
Konstanze
K
Northfield
John
J
Klenerman
Paul
P
Herlyn
Karen
K
Holle
Julia
J
Gottschlich
Stefan
S
Voswinkel
Jan
J
Spies
Thomas
T
Fagin
Ursula
U
Jabs
Wolfram J
WJ
Lamprecht
Peter
P
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
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