Inhibition of natural killer cell activation signals by killer cell immunoglobulin-like receptors (CD158).
The killer cell immunoglobulin-like receptor (KIR) family includes receptors that bind to HLA class I molecules on target cells and inhibit natural killer (NK)-cell cytotoxicity, and receptors such as KIR3DL7 with no known ligand and function. Inhibitory KIR recruit the tyrosine phosphatase SHP-1 to block signals transduced by any one of a number of activation receptors. Inhibition of overall protein tyrosine phosphorylation by SHP-1 during binding of KIR to MHC class I on target cells is selective, suggesting that a limited number of substrates are dephosphorylated by SHP-1. We have chosen to study KIR inhibition as it occurs during binding of KIR to MHC class I on target cells, despite the technical limitations inherent to studies of processes regulated by cell contact. KIR binding to MHC class I on target cells inhibits tyrosine phosphorylation of the activation receptor 2B4 (CD244) and disrupts adhesion of NK cells to target cells. Inhibition of proximal events in NK activation may increase the availability of NK cells by liberating them from non-productive interactions with resistant target cells. As the receptors and the signaling pathways that induce NK cytotoxicity are not fully characterized, elucidation of the inhibitory mechanism employed by KIR may provide insight into NK activation.
Long
E O
EO
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA. elong@nih.gov
Barber
D F
DF
Burshtyn
D N
DN
Faure
M
M
Peterson
M
M
Rajagopalan
S
S
Renard
V
V
Sandusky
M
M
Stebbins
C C
CC
Wagtmann
N
N
Watzl
C
C
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D006680:HLA Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D054340:Receptors, KIR; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; C084093:CD244 protein, human; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D000071176:Signaling Lymphocytic Activation Molecule Family; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases