title: Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked.
abstract: BACKGROUND
  There is limited understanding of the dysregulation of the innate immune system in multiple myeloma (MM). We analysed the expression of the activating receptor NKG2D on NK cells and T cells of MM patients and investigated the impact of soluble versus membrane-bound NKG2D ligands on the expression of NKG2D.
  
  
  METHODS
  NKG2D expression on NK cells and CD8+ alphabeta T cells from patients with MM or monoclonal gammopathy of uncertain significance and healthy controls was examined flow-cytometrically. Sera from patients and controls were analysed for soluble NKG2D ligands (sNKG2D ligands).
  
  
  RESULTS
  Significantly fewer NK cells and CD8+ alphabeta T cells from patients expressed NKG2D compared to healthy controls (NK cells: median 54% interquartile range (IQR) 32-68 versus 71% IQR 44-82%, P = 0.017, CD8+ alphabeta T cells: median 63% IQR 52-81 versus 77% IQR 71-90%, P = 0.018). The sNKG2D ligand sMICA was increased in patients [median 175 (IQR 87-295) pg/ml] versus controls [median 80 (IQR 32-129) pg/ml, P < 0.001], but levels of sMICA did not correlate with NKG2D expression on effector cells. To elucidate the mechanism of NKG2D down-regulation, we incubated lymphocytes from healthy donors in the presence of sNKG2D ligands or in co-culture with MM cell lines. sNKG2D ligands in clinically relevant concentrations did not down-regulate NKG2D expression, but co-culture of effector cells with myeloma cells with high surface expression of NKG2D ligands reduced NKG2D expression significantly.
  
  
  CONCLUSIONS
  These results indicate that MM is associated with a significant reduction in NKG2D expression which may be contact-mediated rather than caused by soluble NKG2D ligands.
authors.affiliation: Transplant Immunology Group, Level 3, St. James's Institute of Oncology, Bexley Wing, St James's University Hospital, Leeds, LS9 7TF, UK. m.lilienfeld.toal@uni-bonn.de
authors.forename: Marie
authors.initials: M
authors.lastname: von Lilienfeld-Toal
authors.forename: Susanne
authors.initials: S
authors.lastname: Frank
authors.forename: Christiane
authors.initials: C
authors.lastname: Leyendecker
authors.forename: Sylvia
authors.initials: S
authors.lastname: Feyler
authors.forename: Sarah
authors.initials: S
authors.lastname: Jarmin
authors.forename: Ruth
authors.initials: R
authors.lastname: Morgan
authors.forename: Axel
authors.initials: A
authors.lastname: Glasmacher
authors.forename: Angela
authors.initials: A
authors.lastname: Märten
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.forename: Gordon
authors.initials: G
authors.lastname: Cook
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D058851:GPI-Linked Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D019139:Tumor Escape
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016693:Receptors, Antigen, T-Cell, alpha-beta; C423230:ULBP2 protein, human