The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells.
Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56(dim) NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patient-derived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression.
El-Sherbiny
Yasser M
YM
Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, UK.
Meade
Josephine L
JL
Holmes
Tim D
TD
McGonagle
Dennis
D
Mackie
Sarah L
SL
Morgan
Ann W
AW
Cook
Gordon
G
Feyler
Sylvia
S
Richards
Stephen J
SJ
Davies
Faith E
FE
Morgan
Gareth J
GJ
Cook
Graham P
GP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D000098862:T Lineage-Specific Activation Antigen 1
D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell