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CUTTING EDGE |
*
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905; and
Section on Lymphocyte Signaling, Cell Biology and Metabolism Branch, National Institutes of Health, Bethesda, MD 20892
Stimulation of NK cell-mediated cytotoxicity involves the
coupling of proximal Src and Syk family protein tyrosine kinases to
downstream effectors. However, the mechanisms linking these second
messenger pathways are incompletely understood. Here, we describe a key
role for the LAT (p36) adaptor protein in human NK cell activation. LAT
is tyrosine phosphorylated upon stimulation of NK cells
through Fc
RIII receptors and following direct contact with
NK-sensitive target cells. This NK stimulation induces the association
of LAT with several phosphotyrosine-containing proteins. In addition to
the biochemical evidence showing LAT involvement in NK cell activation,
a genetic model shows that LAT is required for FcR-dependent
phosphorylation of phospholipase C-. Furthermore,
overexpression of LAT in NK cells leads to increased Ab-dependent
cell-mediated cytotoxicity and "natural cytotoxicity," thus
demonstrating a functional role for LAT in NK cells. These data suggest
that LAT is an important adaptor protein for the regulation of human NK
cell-mediated cytotoxicity.
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