HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C


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 molecules1,2. Here we report the identification of ligands for HLA-E. We constructed tetramers3 in which recombinant HLA-E and β2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones4,5,6. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.

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Figure 1: The HLA-E tetramer binds NK cells and a subset of T cells.
Figure 2: Staining with the HLA-E tetramer is inhibited by anti-CD94 antibodies.
Figure 3: HLA-E binds to the NK cell receptors CD94/NKG2A, CD94/NKG2B and CD94/NKG2C.
Figure 4: HLA-E mediates inhibition of NK cells through interaction with CD94/NKG2A.


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We thank D. Garboczi and D. Wiley for the plasmid containing human β2m; M. Davis for the BirA enzyme; P. Parham for HLA-B*0702 and HLA-B*5801 cDNA; S. Ellis for HLA-G cDNA; B. Corliss for the Ba/F3 cells transfected with the KIR receptors; and Jessica Wyer for the sequencing of HLA-E. A.J.M., V.M.B., C.A.O'C. and G.S.O. are supported by the MRC, D.S.J.A. by a Christopher Welch Scholarship and an O.R.S. Award, and DNAX by Schering Plough Corporation.

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Correspondence to Veronique M. Braud.

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Braud, V., Allan, D., O'Callaghan, C. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998). https://doi.org/10.1038/35869

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