Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked.
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.
von Lilienfeld-Toal
Marie
M
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
Frank
Susanne
S
Leyendecker
Christiane
C
Feyler
Sylvia
S
Jarmin
Sarah
S
Morgan
Ruth
R
Glasmacher
Axel
A
Märten
Angela
A
Schmidt-Wolf
Ingo G H
IG
Brossart
Peter
P
Cook
Gordon
G
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
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