9485206

pubmed:Citation

1

Subsets of T and natural killer (NK) lymphocytes express the CD94-NKG2A heterodimer, a receptor for major histocompatibility complex class I molecules. We show here that engagement of the CD94-NKG2A heterodimer inhibits both antigen-driven tumor necrosis factor (TNF) release and cytotoxicity on melanoma-specific human T cell clones. Similarly, CD16-mediated NK cell cytotoxicity is extinguished by cross-linking of the CD94-NKG2A heterodimer. Combining in vivo and in vitro analysis, we report that both I/VxYxxL immunoreceptor tyrosine-based inhibition motifs (ITIM) present in the NKG2A intracytoplasmic domain associate upon tyrosine phosphorylation with the protein tyrosine phosphatases SHP-1 and SHP-2, but not with the polyinositol phosphatase SHIP Determination of the dissociation constant, using surface plasmon resonance analysis, indicates that NKG2A phospho-ITIM interact directly with the SH2 domains of SHP-1 and SHP-2 with a high affinity. Engagement of the CD94-NKG2A heterodimer therefore appears as a protein-tyrosine phosphatase-based strategy that negatively regulates both antigen-induced T cell response and antibody-induced NK cell cytotoxicity. Our results suggest that this inhibitory pathway sets the threshold of T and NK cell activation.

eng

IM

MEDLINE

0014-2980

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NLM

264-76

pubmed-meshheading:9485206-Amino Acid Sequence, pubmed-meshheading:9485206-Animals, pubmed-meshheading:9485206-Antibody-Dependent Cell Cytotoxicity, pubmed-meshheading:9485206-Antigens, CD, pubmed-meshheading:9485206-Dimerization, pubmed-meshheading:9485206-Humans, pubmed-meshheading:9485206-Immunosuppressive Agents, pubmed-meshheading:9485206-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:9485206-Killer Cells, Natural, pubmed-meshheading:9485206-Kinetics, pubmed-meshheading:9485206-Lectins, C-Type, pubmed-meshheading:9485206-Lymphocyte Activation, pubmed-meshheading:9485206-Lymphocytes, Tumor-Infiltrating, pubmed-meshheading:9485206-Macromolecular Substances, pubmed-meshheading:9485206-Melanoma, pubmed-meshheading:9485206-Membrane Glycoproteins, pubmed-meshheading:9485206-Molecular Sequence Data, pubmed-meshheading:9485206-NK Cell Lectin-Like Receptor Subfamily D, pubmed-meshheading:9485206-Protein Binding, pubmed-meshheading:9485206-Protein Tyrosine Phosphatase, Non-Receptor Type 11, pubmed-meshheading:9485206-Protein Tyrosine Phosphatase, Non-Receptor Type 6, pubmed-meshheading:9485206-Protein Tyrosine Phosphatases, pubmed-meshheading:9485206-Rats, pubmed-meshheading:9485206-Receptors, IgG, pubmed-meshheading:9485206-Recombinant Fusion Proteins, pubmed-meshheading:9485206-T-Lymphocytes, Cytotoxic, pubmed-meshheading:9485206-Tumor Cells, Cultured, pubmed-meshheading:9485206-Tumor Necrosis Factor-alpha

Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases.

Journal Article, Research Support, Non-U.S. Gov't