CD54/ICAM-1 is a costimulator of NK cell-mediated cytotoxicity.
The receptors and the array of cell adhesion molecules regulating MHC-unrestricted cytotoxic activity of NK cells toward tumor targets have not completely characterized. Antibody inhibition studies suggest roles for a number of cell adhesion molecules (CAMs). Recent studies suggest that CAMs can function to stabilize cell-to-cell interactions and/or to provide costimulatory signals that are crucial for T cell activation. It has been difficult to experimentally demonstrate that adhesion molecules also function as costimulators in NK cell-mediated cytotoxicity. We have developed an experimental system using cells transfected with genes encoding huICAM-1 and/or LFA-3 to investigate the function of adhesion molecules. Here we report that neither the expression of transfected ICAM-1 or LFA-3 alone nor the expression of both ICAM-1 and LFA-3, in the absence of MHC class I molecules, converts a murine cell line that is resistant to NK cell-mediated lysis into a susceptible one. We next tested the ability of ICAM-1 or LFA-3-mediated interactions to provide costimulation of NK cell cytolytic activity using a "three cell" experimental system comprising human NK cells, 51C-labeled target cells, and transfected mouse cells as a source of costimulation. The ability of NK cells to lyse K562 cells or anti-CD16-coated target cells was significantly enhanced by the addition of ICAM-1-transfected cells, whereas the addition of cells transfected with LFA-3 or irrelevant genes did not enhance lytic activity. Since the transfected huICAM-1 interacts with NK cells at sites spatially separate from the NK cell-target cell interactions, our data suggest that LFA-1-ICAM-1 or MAC-1-ICAM-1 interactions can provide remote costimulation, via signaling events, to induce cytotoxic activity in NK cells.
Chong
A S
AS
Department of General Surgery, Rush Presbyterian, St. Luke's Medical Center, Chicago, Illinois 60612.
Boussy
I A
IA
Jiang
X L
XL
Lamas
M
M
Graf
L H
LH
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D018801:CD2 Antigens; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007694:Killer Cells, Natural / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008285:Major Histocompatibility Complex / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018968:CD58 Antigens; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D018799:Intercellular Adhesion Molecule-1