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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Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).
Braud, V. M., Allan, D. S. J., Wilson, D. & McMichael, A. J. TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr. Biol. 8, 1–10 (1998).
Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
Phillips, J. H. et al. CD94 and a novel associated protein (94AP) from a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes. Immunity 5, 163–172 (1996).
Sivori, S. et al. CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles: identification of the inhibitory form of D94 by the use of novel monoclonal antibodies.. Eur. J. Immunol. 26, 2487–2492 (1996).
Sivori, S. et al. Inhibitory CD94 molecules identified by the Z199 monoclonal antibody recognize different HLA-class I molecules. Transplant. Proc. 28, 3199–3203 (1996).
Wei, X. H. & Orr, H. T. Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Hum. Immunol. 29, 131–142 (1990).
Connolly, D. J. et al. AcDNA clone encoding the mouse Qa-1a histocompatibility antigen and proposed structure of the putative peptide binding site. J. Immunol. 151, 6089–6098 (1993).
Aldrich, C. J. et al. Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen. Cell 79, 649–658 (1994).
DeCloux, A., Woods, A. S., Cotter, R. J., Soloski, M. J. & Forman, J. Dominance of a single peptide bound to the class IBmolecule, Qa-1b. J. Immunol. 158, 2183–2191 (1997).
Cotterill, L. A. et al. Qa-1 interaction and T cell recognition of the Qa-1 determinant modifier peptide. Eur. J. Immunol. 27, 2123–2132 (1997).
Steven, N. M. et al. Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J. Exp. Med. 185, 1605–1617 (1997).
Aramburu, J. et al. Anovel functional cell surface dimer (Kp43) expressed by natural killer cells and T cell receptor-gamma/delta+ T lymphocytes. I. Inhibition of the IL-2-dependent proliferation by anti-Kp43 monoclonal antibody. J. Immunol. 144, 3238–3247 (1990).
Chang, C. et al. Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. Eur. J. Immunol. 25, 2433–2437 (1995).
Lazetic, S., Chang, C., Houchins, J. P., Lanier, L. L. & Phillips, J. H. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 157, 4741–4745 (1996).
Brooks, A. G., Posch, P. E., Scorzelli, C. J., Borrego, F. & Coligan, J. E. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J. Exp. Med. 185, 795–800 (1997).
Carretero, M. et al. The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27, 563–567 (1997).
Lanier, L. L., Corliss, B. & Phillips, J. H. Arousal and inhibition of human NK cells. Immunol. Rev. 155, 145–154 (1997).
Soderstrom, K., Corliss, B., Lanier, L. L. & Phillips, J. H. CD94/NKG2 is the predominant inhibitory receptor involved in recognition of HLA-G by decidual and peripheral blood NK cells. J. Immunol. 159, 1072–1075 (1997).
Villar, Perez J. J. et al. The CD94/NKG2-A inhibitory receptor complex is involved in natural killer cell-mediated recognition of cells expressing HLA-G1. J. Immunol. 158, 5736–5743 (1997).
Pende, D. et al. HLA-G recognition by human natural killer cells. Involvement of CD94 both as inhibitory and as activating receptor complex. Eur. J. Immunol. 27, 1875–1880 (1997).
Ogg, G. S. et al. Quantification of HIV-specific CTL and plasma load of viral RNA. Science (in the press).
Garboczi, D. N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).
Reyburn, H. T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997).
Houchins, J. jP., Lanier, L. L., Niemi, E. C., Phillips, J. H. & Ryan, J. C. Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C. J. Immunol. 158, 3603–3609 (1997).
Litwin, V., Gumperz, J., Parham, P., Phillips, J. H. & Lanier, L. L. Specificity of HLA class I antigen recognition by human NK clones: evidence for clonal heterogeneity, protection by self and non-self alleles, and influence of the target cell type. J. Exp. Med. 178, 1321–1336 (1993).
Robertson, M. J. et al. Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia. Exp. Hematol. 24, 406–415 (1996).
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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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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