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. 1993 Sep 1;178(3):961–969. doi: 10.1084/jem.178.3.961

Recognition of virus-infected cells by natural killer cell clones is controlled by polymorphic target cell elements

PMCID: PMC2191173  PMID: 8394407

Abstract

Natural killer (NK) cells provide a first line of defense against viral infections. The mechanisms by which NK cells recognize and eliminate infected cells are still largely unknown. To test whether target cell elements contribute to NK cell recognition of virus-infected cells, human NK cells were cloned from two unrelated donors and assayed for their ability to kill normal autologous or allogeneic cells before and after infection by human herpesvirus 6 (HHV-6), a T-lymphotropic herpesvirus. Of 132 NK clones isolated from donor 1, all displayed strong cytolytic activity against the NK-sensitive cell line K562, none killed uninfected autologous T cells, and 65 (49%) killed autologous T cells infected with HHV-6. A panel of representative NK clones from donors 1 and 2 was tested on targets obtained from four donors. A wide heterogeneity was observed in the specificity of lysis of infected target cells among the NK clones. Some clones killed none, some killed only one, and others killed more than one of the different HHV-6- infected target cells. Killing of infected targets was not due to complete absence of class I molecules because class I surface levels were only partially affected by HHV-6 infection. Thus, target cell recognition is not controlled by the effector NK cell alone, but also by polymorphic elements on the target cell that restrict NK cell recognition. Furthermore, NK clones from different donors display a variable range of specificities in their recognition of infected target cells.

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Selected References

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  1. Aoki T., Usuda Y., Miyakoshi H., Tamura K., Herberman R. B. Low natural killer syndrome: clinical and immunologic features. Nat Immun Cell Growth Regul. 1987;6(3):116–128. [PubMed] [Google Scholar]
  2. Balachandran N., Amelse R. E., Zhou W. W., Chang C. K. Identification of proteins specific for human herpesvirus 6-infected human T cells. J Virol. 1989 Jun;63(6):2835–2840. doi: 10.1128/jvi.63.6.2835-2840.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biron C. A., Byron K. S., Sullivan J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989 Jun 29;320(26):1731–1735. doi: 10.1056/NEJM198906293202605. [DOI] [PubMed] [Google Scholar]
  4. Buchwald D., Cheney P. R., Peterson D. L., Henry B., Wormsley S. B., Geiger A., Ablashi D. V., Salahuddin S. Z., Saxinger C., Biddle R. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992 Jan 15;116(2):103–113. doi: 10.7326/0003-4819-116-2-103. [DOI] [PubMed] [Google Scholar]
  5. Caligiuri M., Murray C., Buchwald D., Levine H., Cheney P., Peterson D., Komaroff A. L., Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987 Nov 15;139(10):3306–3313. [PubMed] [Google Scholar]
  6. Chadwick B. S., Miller R. G. Hybrid resistance in vitro. Possible role of both class I MHC and self peptides in determining the level of target cell sensitivity. J Immunol. 1992 Apr 1;148(7):2307–2313. [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. Corbeau P., Devaux C., Kourilsky F., Chermann J. C. An early postinfection signal mediated by monoclonal anti-beta 2 microglobulin antibody is responsible for delayed production of human immunodeficiency virus type 1 in peripheral blood mononuclear cells. J Virol. 1990 Apr;64(4):1459–1464. doi: 10.1128/jvi.64.4.1459-1464.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fleisher G., Starr S., Koven N., Kamiya H., Douglas S. D., Henle W. A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. J Pediatr. 1982 May;100(5):727–730. doi: 10.1016/s0022-3476(82)80572-6. [DOI] [PubMed] [Google Scholar]
  15. Giorda R., Rudert W. A., Vavassori C., Chambers W. H., Hiserodt J. C., Trucco M. NKR-P1, a signal transduction molecule on natural killer cells. Science. 1990 Sep 14;249(4974):1298–1300. doi: 10.1126/science.2399464. [DOI] [PubMed] [Google Scholar]
  16. Giorda R., Trucco M. Mouse NKR-P1. A family of genes selectively coexpressed in adherent lymphokine-activated killer cells. J Immunol. 1991 Sep 1;147(5):1701–1708. [PubMed] [Google Scholar]
  17. Harel-Bellan A., Quillet A., Marchiol C., DeMars R., Tursz T., Fradelizi D. Natural killer susceptibility of human cells may be regulated by genes in the HLA region on chromosome 6. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5688–5692. doi: 10.1073/pnas.83.15.5688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Höglund P., Glas R., Ohlén C., Ljunggren H. G., Kärre K. Alteration of the natural killer repertoire in H-2 transgenic mice: specificity of rapid lymphoma cell clearance determined by the H-2 phenotype of the target. J Exp Med. 1991 Aug 1;174(2):327–334. doi: 10.1084/jem.174.2.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lusso P., De Maria A., Malnati M., Lori F., DeRocco S. E., Baseler M., Gallo R. C. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature. 1991 Feb 7;349(6309):533–535. doi: 10.1038/349533a0. [DOI] [PubMed] [Google Scholar]
  20. Lusso P., Ensoli B., Markham P. D., Ablashi D. V., Salahuddin S. Z., Tschachler E., Wong-Staal F., Gallo R. C. Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6. Nature. 1989 Jan 26;337(6205):370–373. doi: 10.1038/337370a0. [DOI] [PubMed] [Google Scholar]
  21. Lusso P., Malnati M. S., Garzino-Demo A., Crowley R. W., Long E. O., Gallo R. C. Infection of natural killer cells by human herpesvirus 6. Nature. 1993 Apr 1;362(6419):458–462. doi: 10.1038/362458a0. [DOI] [PubMed] [Google Scholar]
  22. Lusso P., Markham P. D., Tschachler E., di Marzo Veronese F., Salahuddin S. Z., Ablashi D. V., Pahwa S., Krohn K., Gallo R. C. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J Exp Med. 1988 May 1;167(5):1659–1670. doi: 10.1084/jem.167.5.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maudsley D. J., Pound J. D. Modulation of MHC antigen expression by viruses and oncogenes. Immunol Today. 1991 Dec;12(12):429–431. doi: 10.1016/0167-5699(91)90013-J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. Natuk R. J., Welsh R. M. Accumulation and chemotaxis of natural killer/large granular lymphocytes at sites of virus replication. J Immunol. 1987 Feb 1;138(3):877–883. [PubMed] [Google Scholar]
  29. Ohlén C., Kling G., Höglund P., Hansson M., Scangos G., Bieberich C., Jay G., Kärre K. Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice. Science. 1989 Nov 3;246(4930):666–668. doi: 10.1126/science.2814488. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Rebaï N., Malissen B. Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. Tissue Antigens. 1983 Aug;22(2):107–117. doi: 10.1111/j.1399-0039.1983.tb01176.x. [DOI] [PubMed] [Google Scholar]
  32. Rook A. H., Masur H., Lane H. C., Frederick W., Kasahara T., Macher A. M., Djeu J. Y., Manischewitz J. F., Jackson L., Fauci A. S. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest. 1983 Jul;72(1):398–403. doi: 10.1172/JCI110981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Salahuddin S. Z., Ablashi D. V., Markham P. D., Josephs S. F., Sturzenegger S., Kaplan M., Halligan G., Biberfeld P., Wong-Staal F., Kramarsky B. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986 Oct 31;234(4776):596–601. doi: 10.1126/science.2876520. [DOI] [PubMed] [Google Scholar]
  34. Sirianni M. C., Soddu S., Malorni W., Arancia G., Aiuti F., Soddus S. Mechanism of defective natural killer cell activity in patients with AIDS is associated with defective distribution of tubulin. J Immunol. 1988 Apr 15;140(8):2565–2568. [PubMed] [Google Scholar]
  35. Storkus W. J., Alexander J., Payne J. A., Dawson J. R., Cresswell P. Reversal of natural killing susceptibility in target cells expressing transfected class I HLA genes. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2361–2364. doi: 10.1073/pnas.86.7.2361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Storkus W. J., Dawson J. R. Target structures involved in natural killing (NK): characteristics, distribution, and candidate molecules. Crit Rev Immunol. 1991;10(5):393–416. [PubMed] [Google Scholar]
  37. 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]
  38. Storkus W. J., Salter R. D., Cresswell P., Dawson J. R. Peptide-induced modulation of target cell sensitivity to natural killing. J Immunol. 1992 Aug 15;149(4):1185–1190. [PubMed] [Google Scholar]
  39. Straus S. E. The chronic mononucleosis syndrome. J Infect Dis. 1988 Mar;157(3):405–412. doi: 10.1093/infdis/157.3.405. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Welsh R. M., Brubaker J. O., Vargas-Cortes M., O'Donnell C. L. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med. 1991 May 1;173(5):1053–1063. doi: 10.1084/jem.173.5.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yokoyama W. M., Ryan J. C., Hunter J. J., Smith H. R., Stark M., Seaman W. E. cDNA cloning of mouse NKR-P1 and genetic linkage with LY-49. Identification of a natural killer cell gene complex on mouse chromosome 6. J Immunol. 1991 Nov 1;147(9):3229–3236. [PubMed] [Google Scholar]

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