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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    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).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).

    ADS  CAS  Article  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  PubMed  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  PubMed  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  PubMed  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  PubMed  Google Scholar 

  16. 16

    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).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    Lanier, L. L., Corliss, B. & Phillips, J. H. Arousal and inhibition of human NK cells. Immunol. Rev. 155, 145–154 (1997).

    CAS  Article  Google Scholar 

  19. 19

    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).

    CAS  PubMed  Google Scholar 

  20. 20

    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).

    Google Scholar 

  21. 21

    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).

    CAS  Article  Google Scholar 

  22. 22

    Ogg, G. S. et al. Quantification of HIV-specific CTL and plasma load of viral RNA. Science (in the press).

  23. 23

    Garboczi, D. N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).

    ADS  CAS  Article  Google Scholar 

  24. 24

    Reyburn, H. T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997).

    ADS  CAS  Article  Google Scholar 

  25. 25

    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).

    CAS  PubMed  Google Scholar 

  26. 26

    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).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Veronique M. Braud.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing