Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Aug 1;182(2):605–609. doi: 10.1084/jem.182.2.605

Amino acid substitutions can influence the natural killer (NK)-mediated recognition of HLA-C molecules. Role of serine-77 and lysine-80 in the target cell protection from lysis mediated by "group 2" or "group 1" NK clones

PMCID: PMC2192139  PMID: 7629517

Abstract

Natural killer (NK) cells have been shown to express a clonally distributed ability to recognize HLA class I alleles. The previously defined NK clones belonging to "group 1" recognize HLA-C*0401 (Cw4) and other HLA-C alleles sharing Asn at position 77 and Lys at position 80. Conversely, the "group 2" NK clones recognize HLA-Cw*0302 (Cw3) and other HLA-C alleles characterized by Ser at position 77 and Asn at position 80. We assessed directly the involvement of these two residues in the capacity of NK cell clones to discriminate between the two groups of HLA-C alleles. To this end, Cw3 and Cw4 alleles were subjected to site-directed mutagenesis. Substitution of the amino acids typical of the Cw3 allele (Ser-77 and Asn-80) with those present in Cw4 (Asn-77 and Lys-80) resulted in a Cw3 mutant that was no longer recognized by group 2 NK cell clones, but that was recognized by group 1 clones. Analysis of Cw3 or Cw4 molecules containing single amino acid substitutions indicates roles for Lys-80 in recognition mediated by group 1 clones and for Ser-77 in recognition mediated by group 2 clones. These results demonstrate that NK-mediated specific recognition of HLA-C allotypes is affected by single natural amino acid substitutions at positions 77 and 80 of the heavy chain.

Full Text

The Full Text of this article is available as a PDF (438.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bottino C., Tambussi G., Ferrini S., Ciccone E., Varese P., Mingari M. C., Moretta L., Moretta A. Two subsets of human T lymphocytes expressing gamma/delta antigen receptor are identifiable by monoclonal antibodies directed to two distinct molecular forms of the receptor. J Exp Med. 1988 Aug 1;168(2):491–505. doi: 10.1084/jem.168.2.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brodsky F. M., Parham P. Monomorphic anti-HLA-A,B,C monoclonal antibodies detecting molecular subunits and combinatorial determinants. J Immunol. 1982 Jan;128(1):129–135. [PubMed] [Google Scholar]
  3. Christiansen F. T., Witt C. S., Ciccone E., Townend D., Pende D., Viale D., Abraham L. J., Dawkins R. L., Moretta L. Human natural killer (NK) alloreactivity and its association with the major histocompatibility complex: ancestral haplotypes encode particular NK-defined haplotypes. J Exp Med. 1993 Sep 1;178(3):1033–1039. doi: 10.1084/jem.178.3.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciccone E., Pende D., Viale O., Than A., Di Donato C., Orengo A. M., Biassoni R., Verdiani S., Amoroso A., Moretta A. Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2). J Exp Med. 1992 Oct 1;176(4):963–971. doi: 10.1084/jem.176.4.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Colonna M., Brooks E. G., Falco M., Ferrara G. B., Strominger J. L. Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. Science. 1993 May 21;260(5111):1121–1124. doi: 10.1126/science.8493555. [DOI] [PubMed] [Google Scholar]
  6. Colonna M., Spies T., Strominger J. L., Ciccone E., Moretta A., Moretta L., Pende D., Viale O. Alloantigen recognition by two human natural killer cell clones is associated with HLA-C or a closely linked gene. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7983–7985. doi: 10.1073/pnas.89.17.7983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ho S. N., Hunt H. D., Horton R. M., Pullen J. K., Pease L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. doi: 10.1016/0378-1119(89)90358-2. [DOI] [PubMed] [Google Scholar]
  8. Long E. O., Rosen-Bronson S., Karp D. R., Malnati M., Sekaly R. P., Jaraquemada D. Efficient cDNA expression vectors for stable and transient expression of HLA-DR in transfected fibroblast and lymphoid cells. Hum Immunol. 1991 Aug;31(4):229–235. doi: 10.1016/0198-8859(91)90092-n. [DOI] [PubMed] [Google Scholar]
  9. Marsh S. G., Krausa P., Bodmer J. G. A preliminary analysis of the 11th International Histocompatibility Workshop monoclonal antibodies. Tissue Antigens. 1990 Oct;36(4):180–186. doi: 10.1111/j.1399-0039.1990.tb01827.x. [DOI] [PubMed] [Google Scholar]
  10. Moretta A., Pantaleo G., Moretta L., Cerottini J. C., Mingari M. C. Direct demonstration of the clonogenic potential of every human peripheral blood T cell. Clonal analysis of HLA-DR expression and cytolytic activity. J Exp Med. 1983 Feb 1;157(2):743–754. doi: 10.1084/jem.157.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Moretta A., Tambussi G., Bottino C., Tripodi G., Merli A., Ciccone E., Pantaleo G., Moretta L. A novel surface antigen expressed by a subset of human CD3- CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function. J Exp Med. 1990 Mar 1;171(3):695–714. doi: 10.1084/jem.171.3.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Moretta A., Vitale M., Bottino C., Orengo A. M., Morelli L., Augugliaro R., Barbaresi M., Ciccone E., Moretta L. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med. 1993 Aug 1;178(2):597–604. doi: 10.1084/jem.178.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Moretta L., Ciccone E., Mingari M. C., Biassoni R., Moretta A. Human natural killer cells: origin, clonality, specificity, and receptors. Adv Immunol. 1994;55:341–380. doi: 10.1016/s0065-2776(08)60513-1. [DOI] [PubMed] [Google Scholar]
  14. Moretta L., Ciccone E., Moretta A., Höglund P., Ohlén C., Kärre K. Allorecognition by NK cells: nonself or no self? Immunol Today. 1992 Aug;13(8):300–306. doi: 10.1016/0167-5699(92)90042-6. [DOI] [PubMed] [Google Scholar]
  15. Saper M. A., Bjorkman P. J., Wiley D. C. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol. 1991 May 20;219(2):277–319. doi: 10.1016/0022-2836(91)90567-p. [DOI] [PubMed] [Google Scholar]
  16. Shimizu Y., DeMars R. Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-C null human cell line. J Immunol. 1989 May 1;142(9):3320–3328. [PubMed] [Google Scholar]
  17. Storkus W. J., Howell D. N., Salter R. D., Dawson J. R., Cresswell P. NK susceptibility varies inversely with target cell class I HLA antigen expression. J Immunol. 1987 Mar 15;138(6):1657–1659. [PubMed] [Google Scholar]
  18. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Zemmour J., Gumperz J. E., Hildebrand W. H., Ward F. E., Marsh S. G., Williams R. C., Parham P. The molecular basis for reactivity of anti-Cw1 and anti-Cw3 alloantisera with HLA-B46 haplotypes. Tissue Antigens. 1992 May;39(5):249–257. doi: 10.1111/j.1399-0039.1992.tb01943.x. [DOI] [PubMed] [Google Scholar]
  20. Zemmour J., Parham P. Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C. J Exp Med. 1992 Oct 1;176(4):937–950. doi: 10.1084/jem.176.4.937. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES