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Fox Chase Cancer Center, Division of Basic Science, Institute for Cancer Research, Philadelphia, PA 19111
Killer cell Ig-like receptors (KIR) are MHC class I-binding
immunoreceptors that can suppress activation of human NK cells through
recruitment of the Src homology 2-containing protein tyrosine
phosphatase-1 (SHP-1) to two immunoreceptor tyrosine-based inhibitory
motifs (ITIMs) in their cytoplasmic domains. KIR2DL4 (2DL4; CD158d) is
a structurally distinct member of the KIR family, which is expressed on
most, if not all, human NK cells. 2DL4 contains only one ITIM in its
cytoplasmic domain and an arginine in its transmembrane region,
suggesting both inhibitory and activating functions. While 2DL4 can
activate IFN-
production, dependent upon the transmembrane arginine,
the function of the single ITIM of 2DL4 remains unknown. In this study,
tandem ITIMs of KIR3DL1 (3DL1) and the single ITIM of 2DL4 were
directly compared in functional and biochemical assays. Using a
retroviral transduction method, we show in human NK cell lines that 1)
the single ITIM of 2DL4 efficiently inhibits natural cytotoxicity
responses; 2) the phosphorylated single ITIM recruits SHP-2 protein
tyrosine phosphatase, but not SHP-1 in NK cells; 3) expression of
dominant-negative SHP-1 does not block the ability of 2DL4 to inhibit
natural cytotoxicity; 4) surprisingly, mutation of the tyrosine within
the single ITIM does not completely abolish inhibitory function; and 5)
this correlates with weak SHP-2 binding to the mutant ITIM of 2DL4 in
NK cells and a corresponding nonphosphorylated ITIM peptide in vitro.
These results reveal new aspects of the KIR-inhibitory pathway in human
NK cells, which are SHP-1 and phosphotyrosine
independent.
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