Cutting edge: HLA-E binds a peptide derived from the ATP-binding cassette transporter multidrug resistance-associated protein 7 and inhibits NK cell-mediated lysis

HLA-E is an MHC class Ib molecule that binds nonamer peptides derived from the leader sequence of MHC class 1a molecules and is the major ligand for CD94/NKG2 receptors found on NK and T cells. Using the MHC class Ia-null cell line 721.221, we find that surface HLA-E increases following heat shock at 42°C and NK cell-mediated lysis is inhibited using heat-stressed 721.221 targets. We have used mass spectrometry to identify and sequence a novel peptide from HLA-E following heat shock, ALALVRMLI, derived from the transmembrane domain of the human ATP-binding cassette protein, multidrug resistance- associated protein, MRP7. Pulsing 721.221 targets with synthetic MRP7 peptide results in strong inhibition of NK cell-mediated lysis that is reversible using anti-CD94 and anti-class I mAbs. This repartis the first to identify a non-MHC leader inhibitory peptide bound to HLA-E and provides insight into the immunoregulatory role of HLA-E during cell stress.