PHOSPHOTYROSINES IN THE KILLER-CELL INHIBITORY RECEPTOR MOTIF OF NKB1ARE REQUIRED FOR NEGATIVE SIGNALING AND FOR ASSOCIATION WITH PROTEIN-TYROSINE-PHOSPHATASE 1C

NKB1 is one member of a growing family elf killer cell, inhibitory rec eptors (KIR). It is expressed on natural killer (NK) cells and T cells , and has been shown to inhibit cytolytic functions of these cells upo n interacting with its Ligand, HLA-B (Bw4). We demonstrate here that t he cytoplasmic region of NKB1 is capable of inhibiting T cell activati on in Jurkat cells. The tyrosine phosphorylation of the NKB1 KIR conse nsus motif, YxxL(x)(26)YxxL, induces an association with the protein t yrosine phosphatase 1C (PTP1C). Importantly, mutation of both tyrosine s in the motif abolished the inhibitory functions of NKB1 and abrogate d PTP1C association. Mutational analysis of the individual tyrosines s uggest that the membrane proximal tyrosine may play a crucial role in mediating the inhibitory signal. These results demonstrate that KIR ca n not only inhibit cytolytic activity, but can also negatively regulat e T cell receptor activation events that lead to downstream gene activ ation, and further supports a model that implicates PTP1C as a mediato r in the KIR inhibitory signal.