IMMUNORECEPTOR DAP12 BEARING A TYROSINE-BASED ACTIVATION MOTIF IS INVOLVED IN ACTIVATING NK CELLS

Natural killer (NK) cells express cell-surface receptors of the immuno globulin and C-type lectin superfamilies that recognize major histocom patibility complex (MHC) class I peptides and inhibit NK-cell-mediated cytotoxicity(1). These inhibitory receptors possess ITIM sequences (f or immunoreceptor tyrosine-based inhibitory motifs) in their cytoplasm ic domains that recruit SH2-domain-containing protein tyrosine phospha tases, resulting in inactivation of NK cells(2-4). Certain isoforms of these NK-cell receptors lack ITIM sequences and it has been proposed that these 'non-inhibitory' receptors may activate,rather than inhibit , NK cells(4-6). Here we show that DAP12, a disulphide-bonded homodime r containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain, non-covalently associates with membrane gly coproteins of the killer-cell inhibitory receptor (KIR) family without an ITIM in their cytoplasmic domain. Crosslinking of KIR-DAP12 comple xes results in cellular activation, as demonstrated by tyrosine phosph orylation of cellular proteins and upregulation of early-activation an tigens. Phosphorylated DAP12 peptides bind ZAP-70 and Syk protein tyro sine kinases, suggesting that the activation pathway is similar to tha t of the T- and B-cell antigen receptors.