Abstract
Killer cell immunoglobulin-like receptors (KIR) inhibit the cytotoxic activity of natural killer (NK) cells by recruitment of the tyrosine phosphatase SHP-1 to immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in the KIR cytoplasmic tail [1]. The precise steps in the NK activation pathway that are inhibited by KIR are yet to be defined. Here, we have studied whether the initial step of adhesion molecule LFA-1-dependent adhesion to target cells was altered by the inhibitory signal. Using stable expression of an HLA-C-specific KIR in the NK cell line YTS [2] and a two-color flow cytometry assay for conjugate formation, we show that adhesion to a target cell expressing cognate HLA-C was disrupted by KIR engagement. Conjugate formation was abruptly interrupted by KIR within less than 5 minutes. Inhibition of adhesion to target cells was mediated by a chimeric KIR molecule carrying catalytically active SHP-1 in place of its cytoplasmic tail. These results suggest that other ITIM-bearing receptors, many of which have no known function, may regulate adhesion in a wide variety of cell types.
MeSH terms
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Abatacept
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Antibodies / pharmacology
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Antigens, CD
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Antigens, Differentiation / pharmacology
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CD28 Antigens / immunology
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CD28 Antigens / physiology
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CTLA-4 Antigen
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Cell Adhesion / drug effects
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Cell Adhesion / physiology*
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Cell Line
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Dose-Response Relationship, Drug
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Flow Cytometry
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Gene Expression
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HLA-C Antigens / genetics
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HLA-C Antigens / physiology
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Humans
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Immunoconjugates*
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Intracellular Signaling Peptides and Proteins
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Killer Cells, Natural / cytology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / physiology*
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Lymphocyte Function-Associated Antigen-1 / immunology
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Lymphocyte Function-Associated Antigen-1 / physiology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology*
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Receptors, KIR
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
Substances
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Antibodies
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Antigens, CD
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Antigens, Differentiation
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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HLA-C Antigens
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HLA-C*02 antigen
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HLA-C*03 antigen
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Immunoconjugates
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Intracellular Signaling Peptides and Proteins
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Lymphocyte Function-Associated Antigen-1
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Receptors, Immunologic
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Receptors, KIR
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Recombinant Fusion Proteins
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Abatacept
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases