HLA-E-BOUND PEPTIDES INFLUENCE RECOGNITION BY INHIBITORY AND TRIGGERING CD94 NKG2 RECEPTORS - PREFERENTIAL RESPONSE TO AN HLA-G-DERIVED NONAMER/

The HLA-E class Ib molecule constitutes a major ligand for the lectin- like CD94/NKG2 natural killer (NK) cell receptors. Specific HLA class I leader sequence-derived nonapeptides bind to endogenous HLA-E molecu les in the HLA-defective cell line 721.221, inducing HLA-E surface exp ression, and promote CD94/NKG2A-mediated recognition. We compared the ability of NK clones which expressed either inhibitory or activating C D94/NKG2 receptors to recognize HLA-E molecules on the surface of 721. 221 cells loaded with a panel of synthetic nonamers derived from the l eader sequences of most HLA class I molecules. Our results support the notion that the primary structure of the HLA-E-bound peptides influen ces CD94/NKG2-mediated recognition, beyond their ability to stabilize surface HLA-E. Further, CD94/NKG2A(+) NK clones appeared more sensitiv e to the interaction with most HLA-E-peptide complexes than did effect or cells expressing the activating CD94/NKG2C receptor. However, a sig nificant exception to this pattern was HLA-E loaded with the HLA-G-der ived nonamer. This complex triggered cytotoxicity very efficiently ove r a wide range of peptide concentrations, suggesting that the HLA-E/G- nonamer complex interacts with the CD94/NKG2 triggering receptor with a significantly higher affinity. These results raise the possibility t hat CD94/NKG2-mediated recognition of HLA-E expressed on extravillous cytotrophoblasts plays an important role in maternal-fetal cellular in teractions.