Natural Killer cell is a major component of the innate immune system. It plays important roles in rejection of cancerous and viral-infected cells. NK cells express numerous surface receptors that can be activating or inhibitory. To investigate how activating and inhibitory NK receptors integrate signals in the decision to activate or to be tolerant, we studied the activating/inhibitory effects of NKG2D-MIC and NKG2A/CD94-peptide-HLA-E pathways, both alone or in combination using human NKL leukemia cell line and in vitro purified protein ligands. Our results demonstrate NKG2D receptors have antibody-induced cell activation effect. MIC ligand induces NKG2D receptor down-regulation on cell surface but alone is not sufficient to induce receptor activation. Surprisingly, NKG2A/CD94 ligand HLA-E/peptide potentiates NKG2D receptor activation. Possible molecular signaling mechanisms will be discussed. Supported by NIH grant AI48675.