HLA-E BINDS TO NATURAL-KILLER-CELL RECEPTORS CD94 NKG2A, CD94/NKG2B AND CD94/NKG2C/

The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules(1,2). Here we repo rt the identification of ligands for HLA-E. We constructed tetramers(3 ) in which recombinant HLA-E and beta 2-microglobulin were refolded wi th an MHC leader-sequence peptide, biotinylated, and conjugated to phy coerythrin-labelled Extravidin. This HLA-E tetramer bound to natural k iller (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B an d CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was en ough to protect target cells from lysis by CD94/NKG2A(+) NK-cell clone s. A subset of HLA class I alleles has been shown to inhibit killing b y CD94/NKG2A(+) NK-cell clones(4-6). Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression con fer resistance to NK-cell-mediated lysis, implying that their action i s mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.