Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Oct 1;176(4):963–971. doi: 10.1084/jem.176.4.963

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)

PMCID: PMC2119377  PMID: 1328466

Abstract

This study was designed to identify the target molecules of the natural killer (NK) cell-mediated recognition of normal allogeneic target cells. As previously shown, the gene(s) governing the first NK-defined allospecificity (specificity 1) were found to be localized in the major histocompatibility complex region between BF gene and HLA-A. In addition, the analysis of a previously described family revealed that a donor (donor 81) was heterozygous for three distinct NK-defined allospecificities (specificities 1, 2, and 5). HLA variants were derived from the B-Epstein-Barr virus cell line of donor 81 by gamma irradiation followed by negative selection using monoclonal antibodies specific for the appropriate HLA allele. Several variants were derived that lacked one or more class I antigen expressions. These variants were analyzed for the susceptibility to lysis by NK clones recognizing different allospecificities. The loss of HLA-A did not modify the phenotype (i.e., "resistance to lysis"). On the other hand, a variant lacking expression of all class I antigens became susceptible to lysis by all alloreactive clones. Variants characterized by the selective loss of class I antigens coded for by the maternal chromosome became susceptible to lysis by anti-2-specific clones. Conversely, variants selectively lacking class I antigens coded for by paternal chromosome became susceptible to lysis by anti-1 and anti-5 clones (but not by anti-2 clones). Since the Cw3 allele was lost in the variant that acquired susceptibility to lysis by anti-2 clones and, in informative families, it was found to cosegregate with the character "resistance to lysis" by anti-2 clones, we analyzed whether Cw3 could represent the element conferring selective resistance to lysis by anti-2 clones. To this end, murine P815 cells transfected with HLA Cw3 (or with other HLA class I genes) were used as target cells in a cytolytic assay in which effector cells were represented by alloreactive NK clones directed against different specificities. Anti-2-specific clones efficiently lysed untransfected or A2-, A3-, and A24-transfected P815 cells, while they failed to lyse Cw3-transfected cells. NK clones recognizing specificities other than specificity 2 lysed untransfected or Cw3- transfected cells. Thus, the loss of Cw3 resulted in the de novo appearance of susceptibility to lysis, and transfection of the HLA- negative P815 cells with Cw3 resulted in resistance to lysis by anti-2 clones. Therefore, we can infer that Cw3 expression on (both human and murine) target cells confers selective protection from lysis mediated by anti-2 NK clones.

Full Text

The Full Text of this article is available as a PDF (935.2 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. Ciccone E., Colonna M., Viale O., Pende D., Di Donato C., Reinharz D., Amoroso A., Jeannet M., Guardiola J., Moretta A. Susceptibility or resistance to lysis by alloreactive natural killer cells is governed by a gene in the human major histocompatibility complex between BF and HLA-B. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9794–9797. doi: 10.1073/pnas.87.24.9794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciccone E., Pende D., Viale O., Di Donato C., Tripodi G., Orengo A. M., Guardiola J., Moretta A., Moretta L. Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans. J Exp Med. 1992 Mar 1;175(3):709–718. doi: 10.1084/jem.175.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ciccone E., Pende D., Viale O., Tambussi G., Ferrini S., Biassoni R., Longo A., Guardiola J., Moretta A., Moretta L. Specific recognition of human CD3-CD16+ natural killer cells requires the expression of an autosomic recessive gene on target cells. J Exp Med. 1990 Jul 1;172(1):47–52. doi: 10.1084/jem.172.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ciccone E., Viale O., Pende D., Malnati M., Biassoni R., Melioli G., Moretta A., Long E. O., Moretta L. Specific lysis of allogeneic cells after activation of CD3- lymphocytes in mixed lymphocyte culture. J Exp Med. 1988 Dec 1;168(6):2403–2408. doi: 10.1084/jem.168.6.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corte G., Calabi F., Damiani G., Bargellesi A., Tosi R., Sorrentino R. Human Ia molecules carrying DC1 determinants differ in both alpha- and beta-subunits from Ia molecules carrying DR determinants. Nature. 1981 Jul 23;292(5821):357–360. doi: 10.1038/292357a0. [DOI] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  9. Janeway C. A., Jr To thine own self be true... Curr Biol. 1991 Aug;1(4):239–241. doi: 10.1016/0960-9822(91)90069-9. [DOI] [PubMed] [Google Scholar]
  10. Ljunggren H. G., Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990 Jul;11(7):237–244. doi: 10.1016/0167-5699(90)90097-s. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Maryanski J. L., Moretta A., Jordan B., De Plaen E., Van Pel A., Boon T., Cerottini J. C. Human T cell recognition of cloned HLA class I gene products expressed on DNA transfectants of mouse mastocytoma P815. Eur J Immunol. 1985 Nov;15(11):1111–1117. doi: 10.1002/eji.1830151109. [DOI] [PubMed] [Google Scholar]
  13. Miller G., Lipman M. Release of infectious Epstein-Barr virus by transformed marmoset leukocytes. Proc Natl Acad Sci U S A. 1973 Jan;70(1):190–194. doi: 10.1073/pnas.70.1.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moretta A., Bottino C., Pende D., Tripodi G., Tambussi G., Viale O., Orengo A., Barbaresi M., Merli A., Ciccone E. Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J Exp Med. 1990 Dec 1;172(6):1589–1598. doi: 10.1084/jem.172.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Parham P., Brodsky F. M. Partial purification and some properties of BB7.2. A cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28. Hum Immunol. 1981 Dec;3(4):277–299. doi: 10.1016/0198-8859(81)90065-3. [DOI] [PubMed] [Google Scholar]
  18. Sire J., Chimini G., Boretto J., Toubert A., Kahn-Perles B., Layet C., Sodoyer R., Lemonnier F., Jordan B. Hybrid genes between HLA-A2 and HLA-A3 constructed by in vivo recombination allow mapping of HLA-A2 and HLA-A3 polymorphic antigenic determinants. J Immunol. 1988 Apr 1;140(7):2422–2430. [PubMed] [Google Scholar]
  19. Storkus W. J., Salter R. D., Alexander J., Ward F. E., Ruiz R. E., Cresswell P., Dawson J. R. Class I-induced resistance to natural killing: identification of nonpermissive residues in HLA-A2. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):5989–5992. doi: 10.1073/pnas.88.14.5989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Turner D. R., Morley A. A. Human somatic mutation at the autosomal HLA-A locus. Prog Clin Biol Res. 1990;340C:37–46. [PubMed] [Google Scholar]
  22. Vartdal F., Kvalheim G., Lea T. E., Bosnes V., Gaudernack G., Ugelstad J., Albrechtsen D. Depletion of T lymphocytes from human bone marrow. Use of magnetic monosized polymer microspheres coated with T-lymphocyte-specific monoclonal antibodies. Transplantation. 1987 Mar;43(3):366–371. [PubMed] [Google Scholar]
  23. Zemmour J., Parham P. HLA class I nucleotide sequences, 1991. Immunogenetics. 1991;33(5-6):310–320. doi: 10.1007/BF00216690. [DOI] [PubMed] [Google Scholar]

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

RESOURCES