Origin and functions of human natural killer cells

  • L. Moretta
  • E. Ciccone
  • A. Poggi
  • M. C. Mingari
  • A. Moretta


Recent data have substantially modified our view of natural killer cells. Although maturation of natural killer cells occurs in the absence of a functional thymus, we have shown that clonogenic precursors capable of differentiating into mature CD3−16+56+ natural killer cells exist in CD3−4−8−16− populations isolated from human thymus. Analysis of peripheral bloodderived natural killer clones showed that they can lyse normal cells (e.g., phytohemagglutinin-induced blasts) isolated from some individuals. Importantly, natural killer clones isolated from single individuals displayed different patterns of cytolytic activity against a panel of normal allogeneic cells. These data suggested the existence of a natural killer cell repertoire. A number of observations have revealed that the expression of given HLA class I alleles protects target cells from lysis by different groups of natural killer clones. Evidence has been gained by genetic analysis of the determinants responsible for susceptibility/resistance to lysis by natural killer clones together with analysis, as target cells, of HLA-defective variants or HLA transfectants. Thus, natural killer cells were found to express a clonally distributed ability to recognize HLA class I alleles. The selection of new monoclonal antibodies directed against members of a novel family of natural killer specific p58 molecules allowed the identification of the putative natural killer receptors for different MHC class I alleles. Firstly, a correlation was established between the expression of given p58 molecules (e.g., EB6 and GL183) and the class I alleles recognized. Secondly, anti-p58 monoclonal antibodies restored the natural killer-mediated lysis of class I-protected cells. A similar effect was obtained by inducing modulation of p58 surface molecules with anti-p58 monoclonal antibodies. The implications of these receptor/ligand interactions in the physiopathological behavior of natural killer cells are discussed.

Key words

Natural killer cells Natural killer receptors MHC class I Natural killer repertoire 


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  1. 1.
    Trinchieri G. Biology of natural killer cells. Adv Immunol 1989; 47:187.PubMedGoogle Scholar
  2. 2.
    Lanier LL, Phillips J, Hackett J, Tutt M, Kumar V. Natural killer cells: definition of a cell type rather than a function. J Immunol 1986; 137:2375.Google Scholar
  3. 3.
    Kraft D, Lanier LL. The Fc receptor for IgG on human natural killer cells: phenotypic, functional and comparative studies using monoclonal antibodies. J Immunol 1984; 133: 180.PubMedGoogle Scholar
  4. 4.
    Griffin JD, Hercend T, Beveridge R, Schlossman SF. Characterization of an antigen expressed on human natural killer cells. J Immunol 1983; 130:2947.PubMedGoogle Scholar
  5. 5.
    McGarry RC, Pinto A, Hammersley-Straw DR, Trevenen CL. Expression of markers shared between human natural killer cells and neuroblastoma lines. Cancer Immunol Immunother 1988; 27:47.PubMedCrossRefGoogle Scholar
  6. 6.
    Lanier LL et al. Molecular and functional analysis of human NK-cells associated neural cell adhesion molecule (N-CAM/DC56). J Immunol 1991; 146:4421.PubMedGoogle Scholar
  7. 7.
    Lanier LL, Le AM, Civin CI, Loke MR, Phillips JH. The relationship of CD16 (Leu11) and Leu19 (NKH1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 1986; 136:4480.PubMedGoogle Scholar
  8. 8.
    Shubert W, Zimmermann K, Cramer M, Powitz S. Lymphocyte antigen Leu-19 as a molecular marker of regeneration in human skeletal muscle. Proc Natl Acad Sci USA 1989; 86:307.CrossRefGoogle Scholar
  9. 9.
    Saksela E, Timonen R, Ranki A, Häyry P. Morphological and functional characterization of isolated effector cells responsible for human natural killer activity to fetal fibroblasts and to cultured cell line targets. Immunol Rev 1979; 44:71.PubMedCrossRefGoogle Scholar
  10. 10.
    Herberman RB, Nunn MF, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngenic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 1975; 16:230.PubMedCrossRefGoogle Scholar
  11. 11.
    Hackett JJ, Bosma GC, Bosma MJ, Bennet M, Kumar V. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes. Proc Natl Acad Sci USA 1986; 83:3427.PubMedCrossRefGoogle Scholar
  12. 12.
    Dorshkind K, Pollack SB, Bosma MJ, Phillips RA. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (Scid). J Immunol 1985; 134:3798.PubMedGoogle Scholar
  13. 13.
    Moretta A, Pantaleo G, Moretta L, Mingari MC, Cerottini JC. 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; 157:743.PubMedCrossRefGoogle Scholar
  14. 14.
    Pantaleo G, Zocchi MR, Ferrini S, Poggi A, Tambussi G, Bottino C, Moretta L, Moretta A. Human cytolytic cell clones lacking surface expression of T cell receptorα/β orγ/δ. Evidence that surface structures other than CD3 or CD2 molecules are required for signal transduction. J Exp Med 1988; 168:13.PubMedCrossRefGoogle Scholar
  15. 15.
    Ciccone E, Viale O, Pende D, Malnati M, Biassoni R, Melioli G, Moretta A, Long EO, Moretta L. Specific lysis of allogeneic cells after activation of CD3—lymphocytes in mixed lymphocyte culture. J Exp Med 1988; 168:2403.PubMedCrossRefGoogle Scholar
  16. 16.
    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+NK cells requires the expression of an autosomic recessive gene on target cells. J Exp Med 1990; 172:47.PubMedCrossRefGoogle Scholar
  17. 17.
    Ciccone E, Pende D, Viale O, Di Donato C, Tripodi G, Orengo AM, Guardiola J, Moretta A, Moretta L. Evidence of natural killer (NK) cell repertoire for (allo)antigen recognition: definition of five distinct NK-determined allospecificities in humans. J Exp Med 1992; 175:709.PubMedCrossRefGoogle Scholar
  18. 18.
    Moretta L, Ciccone E, Moretta A, Höglund P, Öhlen C, Karre K. Allorecognition by NK cells: nonself or no self? Immunol Today 1992; 13:300.PubMedCrossRefGoogle Scholar
  19. 19.
    Ciccone E, Colonna M, Viale O, Pende D, Di Donato C, Reinherz E, Amoroso A, Jeannet M, Guardiola J, Moretta A, Spies T, Strominger J, Moretta L. Susceptibility or resistance to lysis by alloreactive NK cells is governed by a gene in the human major histocompatibility complex between Bf and HLA-B. Proc Natl Acad Sci USA 1991; 87:9794.CrossRefGoogle Scholar
  20. 20.
    Ciccone E, Pende D, Viale O, Di Donato C, Orengo AM, Biassoni R, Vardiani S, Amoroso A, Moretta A, Moretta L. Involvement of HLA class I alleles in NK cell specific function: expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2). J Exp Med 1992; 176:963.PubMedCrossRefGoogle Scholar
  21. 21.
    Lijunggren HG, Karre K. In search of the “missing self”: MHC molecules and NK cell recognition. Immunol Today 1990; 11:237.CrossRefGoogle Scholar
  22. 22.
    Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R, Barbaresi M, Ciccone E, Moretta L. P58 molecules as putative receptors for 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; 178: 597.PubMedCrossRefGoogle Scholar
  23. 23.
    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; 171:695.PubMedCrossRefGoogle Scholar
  24. 24.
    Moretta A, Bottino C, Pende D, Tripodi G, Tambussi G, Viale O, Orengo AM, Barbaresi M, Merli A, Ciccone E, Moretta L. Identification of four subsets of human CD3–CD16+ 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; 172: 1589.PubMedCrossRefGoogle Scholar
  25. 25.
    Herberman RB, editor. NK cells and other natural effector cells, New York: Academic Press, 1982.Google Scholar
  26. 26.
    Lanier LL, Cwirla S, Phillips JH. Genomic organization of T cell γ genes in human peripheral blood natural killer cells. J Immunol 1986; 137:3375.PubMedGoogle Scholar
  27. 27.
    Lanier LL, Cwirla S, Federspiel N, Phillips JH. Human natural killer cells isolated from peripheral blood do not rearrange T cell antigen receptorβ chain genes. J Exp Med 1986; 163: 209.PubMedCrossRefGoogle Scholar
  28. 28.
    Tutt MM, Kuziel WA, Hackett J, Bennet M, Tucker PW, Kumar V. Murine natural killer cells do not express functional transcripts of theα−, β−, orγ-chain genes of the T cell receptor. J Immunol 1986; 137:2998.PubMedGoogle Scholar
  29. 29.
    Garni-Wagner BA, Witte PL, Tutt MM, Kziel WA, Tucker PW, Bennet M, Kumar V. Natural killer cells in the thymus. Studies in mice with severe combined immune deficiency. J Immunol 1990; 144: 796.PubMedGoogle Scholar
  30. 30.
    Poggi A, Biassoni R, Pella N, Paolieri F, Bellomo R, Bertolini L, Moretta L, Mingari MC. In vitro expansion of CD3/TCR—human thymocyte populations that selectively lack CD3 gene expression: a phenotypic and a functional analysis. J Exp Med 1990; 172: 1409.PubMedCrossRefGoogle Scholar
  31. 31.
    Mingari MC, Poggi A, Biassoni R, Bellomo R, Ciccone E, Pella N, Morelli L, Verdiani S, Moretta A, Moretta L. In vitro proliferation and cloning of CD3–CD16+ cells from human thymocyte precursors. J Exp Med 1991; 174:21.PubMedCrossRefGoogle Scholar
  32. 32.
    De la Hera A, Marston W, Aranda C, Toribio ML, Martinez AC. Thymic stroma is required for the development of human T cell lineages in vitro. Int Immunol 1991; 1:471.CrossRefGoogle Scholar
  33. 33.
    Poggi A, Sargiacomo M, Biassoni R, Pella N, Sivori S, Revello V, Costa P, Valtieri M, Russo G, Mingari MC, Peschle C, Moretta L. Extrathymic differentiation of T lymphocytes and natural killer cells from human embryonic liver precursors. Proc Natl Acad Sci USA 1993; 90:4465.PubMedCrossRefGoogle Scholar
  34. 34.
    Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. A population of early fetal thymocytes expressing FcγRII/III contains precursors of T lymphocytes and natural killer cells. Cell 1992; 69:139.PubMedCrossRefGoogle Scholar
  35. 35.
    Mingari MC, Varese P, Bottino C, Melioli G, Moretta A, Moretta L. Clonal analysis of CD4–CD8− human thymocytes expressing a T cell receptorγ/δ chain. Direct evidence for the de novo expression of CD8 surface antigen and of cytolytic activity against tumor targets. Eur J Immunol 1988; 18: 1831.PubMedCrossRefGoogle Scholar
  36. 36.
    Moretta L, Ciccone E, Mingari MC, Biassoni R, Moretta L. Human NK cells: origin, clonality, specificity and receptors. Adv Immunol 1993; 55:341.CrossRefGoogle Scholar
  37. 37.
    Raulet DH. A sense of something missing. Nature 1992; 358:21.PubMedCrossRefGoogle Scholar
  38. 38.
    Karre K. An unexpected petition for pardon. 1992; 2:613.Google Scholar
  39. 39.
    Versteeg R, Kruse-Wolters KM, Plomp AC, Leeuwen A van, Stam NJ, Ploegh HL, Ruiter DJ, Schrier PI. Suppression of class I human histocompatibility leukocyte antigen by c-myc is locus specific. J Exp Med 1989; 170:621.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • L. Moretta
    • 1
    • 2
  • E. Ciccone
    • 1
  • A. Poggi
    • 1
  • M. C. Mingari
    • 3
  • A. Moretta
    • 1
    • 4
  1. 1.Istituto Nazionale per la Ricerca sul CancroGenovaItaly
  2. 2.Dipartimento di Medicina ed Oncologia SperimentaleUniversità di TorinoTorinoItaly
  3. 3.Istituto di Oncologia Clinica e SperimentaleUniversità di GenovaGenovaItaly
  4. 4.Istituto di Istologia ed Embriologia GeneraleUniversità di GenovaGenovaItaly

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