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.
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.
Le Dréan
E
E
INSERM U463, Institut de Biologie et Faculté des Sciences, Nantes, France.
Vély
F
F
Olcese
L
L
Cambiaggi
A
A
Guia
S
S
Krystal
G
G
Gervois
N
N
Moretta
A
A
Jotereau
F
F
Vivier
E
E
D000595:Amino Acid Sequence; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D015703:Antigens, CD / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D007700:Kinetics; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating; D046911:Macromolecular Substances; D008545:Melanoma / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D008969:Molecular Sequence Data; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C497869:KLRD1 protein, human; C497871:Klrd1 protein, rat; D037181:Lectins, C-Type; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; 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; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat