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*
Amgen Institute, and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; and
Department of Oral Biochemistry, Kanagawa Dental College, Kanagawa, Japan
IL-2-activated NK cells exhibit cytotoxic activity against a wide
variety of tumor cells in a non-MHC-restricted fashion and in the
absence of prior sensitization. The molecular mechanisms that regulate
the cytotoxicity and attachment of activated killer cells to tumor
target cells are not known. We provide genetic evidence in
CD44-/- and LFA-1-/- mice that the
cell adhesion receptors LFA-1 and CD44 regulate the cytotoxic activity
of IL-2-activated NK cells against a variety of different tumor cells.
This defect in cytotoxicity was significantly enhanced in mice that
carried a double mutation of both CD44 and LFA-1. In vitro
differentiation, TNF-
and IFN-
production, and expression of the
cytolytic effector molecules perforin and Fas-L were comparable among
IL-2-activated NK cells from LFA-1-/-,
CD44-/-, CD44-/-LFA-1-/-, and
control mice. However, CD44-/-, LFA-1-/-,
and CD44-/-LFA-1-/- IL-2-activated NK cells
showed impaired binding and conjugate formation with target cells. We
also show that hyaluronic acid is the principal ligand on tumor cells
for CD44-mediated cytotoxicity of IL-2-activated NK cells. These
results provide the first genetic evidence of the role of adhesion
receptors in IL-2-activated NK killing. These data also indicate that
distinct adhesion receptors cooperate to mediate binding between
effector and target cells required for the initiation of "natural"
cytotoxicity.
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