Skip to main content
PMC home page
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1994 Mar;1(2):125–133. doi: 10.1128/cdli.1.2.125-133.1994

Role of human natural killer cells in health and disease.

T L Whiteside 1, R B Herberman 1
PMCID: PMC368214  PMID: 7496932

Abstract

Natural killer (NK) cells, the CD3- CD56+ CD16+ subset of peripheral blood lymphocytes, have long been known to be involved in non-major histocompatibility complex-restricted natural immunity to virally infected and malignant target cells. The association of abnormalities in NK cell numbers or functions with a broad spectrum of human diseases has been more clearly defined in recent years as a result of the improved knowledge of NK cell physiology and advances in monitoring of NK cell functions in health and disease. The ability to reliably measure changes in NK activity and/or numbers during the course of disease or response to treatment has focused attention on the role of the NK cell in disease pathogenesis. The improved understanding of NK cell deficiency in disease has opened a way for therapies specifically designed to improve NK cell function. The therapeutic use of biologic response modifiers capable of augmenting NK cell activity in vivo and of adoptive transfer of highly enriched, activated autologous NK cells in diseases such as cancer and AIDS is being evaluated. The importance of NK cells in health and the consequences of NK cell deficiency or excess are likely to be more extensively monitored in the future.

Full text

PDF
125

Selected References

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

  1. Allavena P., Paganin C., Martin-Padura I., Peri G., Gaboli M., Dejana E., Marchisio P. C., Mantovani A. Molecules and structures involved in the adhesion of natural killer cells to vascular endothelium. J Exp Med. 1991 Feb 1;173(2):439–448. doi: 10.1084/jem.173.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson P., Caligiuri M., O'Brien C., Manley T., Ritz J., Schlossman S. F. Fc gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2274–2278. doi: 10.1073/pnas.87.6.2274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson P., Caligiuri M., Ritz J., Schlossman S. F. CD3-negative natural killer cells express zeta TCR as part of a novel molecular complex. Nature. 1989 Sep 14;341(6238):159–162. doi: 10.1038/341159a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bonavida B., Wright S. C. Role of natural killer cytotoxic factors in the mechanism of target-cell killing by natural killer cells. J Clin Immunol. 1986 Jan;6(1):1–8. doi: 10.1007/BF00915358. [DOI] [PubMed] [Google Scholar]
  6. Bukowski J. F., Warner J. F., Dennert G., Welsh R. M. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J Exp Med. 1985 Jan 1;161(1):40–52. doi: 10.1084/jem.161.1.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Caligiuri M. A., Murray C., Robertson M. J., Wang E., Cochran K., Cameron C., Schow P., Ross M. E., Klumpp T. R., Soiffer R. J. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993 Jan;91(1):123–132. doi: 10.1172/JCI116161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Caligiuri M. A., Zmuidzinas A., Manley T. J., Levine H., Smith K. A., Ritz J. Functional consequences of interleukin 2 receptor expression on resting human lymphocytes. Identification of a novel natural killer cell subset with high affinity receptors. J Exp Med. 1990 May 1;171(5):1509–1526. doi: 10.1084/jem.171.5.1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cassatella M. A., Anegón I., Cuturi M. C., Griskey P., Trinchieri G., Perussia B. Fc gamma R(CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. Role of Ca2+ in Fc gamma R(CD16)-induced transcription and expression of lymphokine genes. J Exp Med. 1989 Feb 1;169(2):549–567. doi: 10.1084/jem.169.2.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chang Z. L., Whiteside T. L., Herberman R. B. Immunoregulatory role of in vitro differentiated macrophages on human natural killer (NK)-cell activity. Cell Immunol. 1990 Jan;125(1):183–196. doi: 10.1016/0008-8749(90)90073-z. [DOI] [PubMed] [Google Scholar]
  11. Cuturi M. C., Anegón I., Sherman F., Loudon R., Clark S. C., Perussia B., Trinchieri G. Production of hematopoietic colony-stimulating factors by human natural killer cells. J Exp Med. 1989 Feb 1;169(2):569–583. doi: 10.1084/jem.169.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Djeu J. Y., Blanchard D. K. Regulation of human polymorphonuclear neutrophil (PMN) activity against Candida albicans by large granular lymphocytes via release of a PMN-activating factor. J Immunol. 1987 Oct 15;139(8):2761–2767. [PubMed] [Google Scholar]
  13. Fletcher M. A., Baron G. C., Ashman M. R., Fischl M. A., Klimas N. G. Use of whole blood methods in assessment of immune parameters in immunodeficiency states. Diagn Clin Immunol. 1987;5(2):69–81. [PubMed] [Google Scholar]
  14. Gismondi A., Morrone S., Humphries M. J., Piccoli M., Frati L., Santoni A. Human natural killer cells express VLA-4 and VLA-5, which mediate their adhesion to fibronectin. J Immunol. 1991 Jan 1;146(1):384–392. [PubMed] [Google Scholar]
  15. Haller O., Kiessling R., Orn A., Wigzell H. Generation of natural killer cells: an autonomous function of the bone marrow. J Exp Med. 1977 May 1;145(5):1411–1416. doi: 10.1084/jem.145.5.1411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hata K., Van Thiel D. H., Herberman R. B., Whiteside T. L. Natural killer activity of human liver-derived lymphocytes in various liver diseases. Hepatology. 1991 Sep;14(3):495–503. [PubMed] [Google Scholar]
  17. Hata K., Zhang X. R., Iwatsuki S., Van Thiel D. H., Herberman R. B., Whiteside T. L. Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin Immunol Immunopathol. 1990 Sep;56(3):401–419. doi: 10.1016/0090-1229(90)90160-r. [DOI] [PubMed] [Google Scholar]
  18. Henney C. S., Kuribayashi K., Kern D. E., Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981 May 28;291(5813):335–338. doi: 10.1038/291335a0. [DOI] [PubMed] [Google Scholar]
  19. Herberman R. R., Ortaldo J. R., Bonnard G. D. Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature. 1979 Jan 18;277(5693):221–223. doi: 10.1038/277221a0. [DOI] [PubMed] [Google Scholar]
  20. Hercend T., Farace F., Baume D., Charpentier F., Droz J. P., Triebel F., Escudier B. Immunotherapy with lymphokine-activated natural killer cells and recombinant interleukin-2: a feasibility trial in metastatic renal cell carcinoma. J Biol Response Mod. 1990 Dec;9(6):546–555. [PubMed] [Google Scholar]
  21. Hercend T., Schmidt R. E. Characteristics and uses of natural killer cells. Immunol Today. 1988 Oct;9(10):291–293. doi: 10.1016/0167-5699(88)91317-5. [DOI] [PubMed] [Google Scholar]
  22. Hoofnagle J. H., Peters M., Mullen K. D., Jones D. B., Rustgi V., Di Bisceglie A., Hallahan C., Park Y., Meschievitz C., Jones E. A. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology. 1988 Nov;95(5):1318–1325. doi: 10.1016/0016-5085(88)90367-8. [DOI] [PubMed] [Google Scholar]
  23. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  24. Imamura N., Kusunoki Y., Kawa-Ha K., Yumura K., Hara J., Oda K., Abe K., Dohy H., Inada T., Kajihara H. Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells. Br J Haematol. 1990 May;75(1):49–59. doi: 10.1111/j.1365-2141.1990.tb02615.x. [DOI] [PubMed] [Google Scholar]
  25. Kirkwood J. M., Ernstoff M. S. Interferons in the treatment of human cancer. J Clin Oncol. 1984 Apr;2(4):336–352. doi: 10.1200/JCO.1984.2.4.336. [DOI] [PubMed] [Google Scholar]
  26. Lanier L. L., Cwirla S., Federspiel N., Phillips J. H. Human natural killer cells isolated from peripheral blood do not rearrange T cell antigen receptor beta chain genes. J Exp Med. 1986 Jan 1;163(1):209–214. doi: 10.1084/jem.163.1.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lanier L. L., Le A. M., Civin C. I., Loken M. R., Phillips J. H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol. 1986 Jun 15;136(12):4480–4486. [PubMed] [Google Scholar]
  28. Levy S. M., Herberman R. B., Simons A., Whiteside T., Lee J., McDonald R., Beadle M. Persistently low natural killer cell activity in normal adults: immunological, hormonal and mood correlates. Nat Immun Cell Growth Regul. 1989;8(3):173–186. [PubMed] [Google Scholar]
  29. Lotzová E., Savary C. A. Generation of NK cell activity from human bone marrow. J Immunol. 1987 Jul 1;139(1):279–284. [PubMed] [Google Scholar]
  30. Matera L., Muccioli G., Cesano A., Bellussi G., Genazzani E. Prolactin receptors on large granular lymphocytes: dual regulation by cyclosporin A. Brain Behav Immun. 1988 Mar;2(1):1–10. doi: 10.1016/0889-1591(88)90001-3. [DOI] [PubMed] [Google Scholar]
  31. Melder R. J., Walker E., Herberman R. B., Whiteside T. L. Adhesion characteristics of human interleukin 2-activated natural killer cells. Cell Immunol. 1991 Jan;132(1):177–192. doi: 10.1016/0008-8749(91)90017-6. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Moretta L., Ciccone E., Pende D., Tripodi G., Bottino C., Moretta A. Human natural killer cells: clonally distributed specific functions and triggering surface molecules. Lab Invest. 1992 Feb;66(2):138–142. [PubMed] [Google Scholar]
  34. Murphy W. J., Reynolds C. W., Tiberghien P., Longo D. L. Natural killer cells and bone marrow transplantation. J Natl Cancer Inst. 1993 Sep 15;85(18):1475–1482. doi: 10.1093/jnci/85.18.1475. [DOI] [PubMed] [Google Scholar]
  35. Nagler A., Lanier L. L., Cwirla S., Phillips J. H. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989 Nov 15;143(10):3183–3191. [PubMed] [Google Scholar]
  36. Nagler A., Lanier L. L., Phillips J. H. Constitutive expression of high affinity interleukin 2 receptors on human CD16-natural killer cells in vivo. J Exp Med. 1990 May 1;171(5):1527–1533. doi: 10.1084/jem.171.5.1527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ortaldo J. R., Mason A., Overton R. Lymphokine-activated killer cells. Analysis of progenitors and effectors. J Exp Med. 1986 Oct 1;164(4):1193–1205. doi: 10.1084/jem.164.4.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Perussia B. Lymphokine-activated killer cells, natural killer cells and cytokines. Curr Opin Immunol. 1991 Feb;3(1):49–55. doi: 10.1016/0952-7915(91)90076-d. [DOI] [PubMed] [Google Scholar]
  39. Pricop L., Galatiuc C., Manciulea M., DeLeo A., Sulica A., Herberman R. B., Whiteside T. L. Expression of Fc mu receptors on human natural killer cells. Clin Immunol Immunopathol. 1991 Jun;59(3):355–367. doi: 10.1016/0090-1229(91)90031-5. [DOI] [PubMed] [Google Scholar]
  40. Pricop L., Rabinowich H., Morel P. A., Sulica A., Whiteside T. L., Herberman R. B. Characterization of the Fc mu receptor on human natural killer cells. Interaction with its physiologic ligand, human normal IgM, specificity of binding, and functional effects. J Immunol. 1993 Sep 15;151(6):3018–3029. [PubMed] [Google Scholar]
  41. Rabinowich H., Sedlmayr P., Herberman R. B., Whiteside T. L. Response of human NK cells to IL-6 alterations of the cell surface phenotype, adhesion to fibronectin and laminin, and tumor necrosis factor-alpha/beta secretion. J Immunol. 1993 Jun 1;150(11):4844–4855. [PubMed] [Google Scholar]
  42. Rabinowich H., Vitolo D., Altarac S., Herberman R. B., Whiteside T. L. Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. J Immunol. 1992 Jul 1;149(1):340–349. [PubMed] [Google Scholar]
  43. Robertson M. J., Caligiuri M. A., Manley T. J., Levine H., Ritz J. Human natural killer cell adhesion molecules. Differential expression after activation and participation in cytolysis. J Immunol. 1990 Nov 15;145(10):3194–3201. [PubMed] [Google Scholar]
  44. Robertson M. J., Manley T. J., Donahue C., Levine H., Ritz J. Costimulatory signals are required for optimal proliferation of human natural killer cells. J Immunol. 1993 Mar 1;150(5):1705–1714. [PubMed] [Google Scholar]
  45. Robertson M. J., Ritz J. Biology and clinical relevance of human natural killer cells. Blood. 1990 Dec 15;76(12):2421–2438. [PubMed] [Google Scholar]
  46. Rosenberg S. A., Lotze M. T., Muul L. M., Chang A. E., Avis F. P., Leitman S., Linehan W. M., Robertson C. N., Lee R. E., Rubin J. T. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987 Apr 9;316(15):889–897. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  47. Rosenberg S. A., Lotze M. T., Yang J. C., Aebersold P. M., Linehan W. M., Seipp C. A., White D. E. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989 Oct;210(4):474–485. doi: 10.1097/00000658-198910000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sandor M., Lynch R. G. The biology and pathology of Fc receptors. J Clin Immunol. 1993 Jul;13(4):237–246. doi: 10.1007/BF00919382. [DOI] [PubMed] [Google Scholar]
  49. Santoni A., Gismondi A., Morrone S., Procopio A., Modesti A., Scarpa S., D'Orazi G., Piccoli M., Frati L. Rat natural killer cells synthesize fibronectin. Possible involvement in the cytotoxic function. J Immunol. 1989 Oct 1;143(7):2415–2421. [PubMed] [Google Scholar]
  50. Skoner D. P., Whiteside T. L., Wilson J. W., Doyle W. J., Herberman R. B., Fireman P. Effect of rhinovirus 39 infection on cellular immune parameters in allergic and nonallergic subjects. J Allergy Clin Immunol. 1993 Nov;92(5):732–743. doi: 10.1016/0091-6749(93)90017-a. [DOI] [PubMed] [Google Scholar]
  51. Storkus W. J., Alexander J., Payne J. A., Cresswell P., Dawson J. R. The alpha 1/alpha 2 domains of class I HLA molecules confer resistance to natural killing. J Immunol. 1989 Dec 1;143(11):3853–3857. [PubMed] [Google Scholar]
  52. 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]
  53. Sulica A., Galatiuc C., Manciulea M., Bancu A. C., DeLeo A., Whiteside T. L., Herberman R. B. Regulation of human natural cytotoxicity by IgG. IV. Association between binding of monomeric IgG to the Fc receptors on large granular lymphocytes and inhibition of natural killer (NK) cell activity. Cell Immunol. 1993 Apr 1;147(2):397–410. doi: 10.1006/cimm.1993.1079. [DOI] [PubMed] [Google Scholar]
  54. Taniguchi T., Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. doi: 10.1016/0092-8674(93)90152-g. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. Vitolo D., Vujanovic N. L., Rabinowich H., Schlesinger M., Herberman R. B., Whiteside T. L. Rapid Il-2-induced adherence of human natural killer cells. Expression of mRNA for cytokines and IL-2 receptors in adherent NK cells. J Immunol. 1993 Aug 15;151(4):1926–1937. [PubMed] [Google Scholar]
  57. Voss S. D., Sondel P. M., Robb R. J. Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R. J Exp Med. 1992 Aug 1;176(2):531–541. doi: 10.1084/jem.176.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Weil-Hillman G., Voss S. D., Fisch P., Schell K., Hank J. A., Sosman J. A., Sugamura K., Sondel P. M. Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptor and maintain the p55 (TAC) negative phenotype. Cancer Res. 1990 May 1;50(9):2683–2691. [PubMed] [Google Scholar]
  59. Welsh R. M. Regulation of virus infections by natural killer cells. A review. Nat Immun Cell Growth Regul. 1986;5(4):169–199. [PubMed] [Google Scholar]
  60. Whiteside T. L., Bryant J., Day R., Herberman R. B. Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay. J Clin Lab Anal. 1990;4(2):102–114. doi: 10.1002/jcla.1860040207. [DOI] [PubMed] [Google Scholar]
  61. Whiteside T. L., Herberman R. B. Extravasation of antitumor effector cells. Invasion Metastasis. 1992;12(2):128–146. [PubMed] [Google Scholar]
  62. Whiteside T. L., Herberman R. B. The biology of human natural killer cells. Ann Ist Super Sanita. 1990;26(3-4):335–348. [PubMed] [Google Scholar]
  63. Whiteside T. L., Herberman R. B. The role of natural killer cells in human disease. Clin Immunol Immunopathol. 1989 Oct;53(1):1–23. doi: 10.1016/0090-1229(89)90096-2. [DOI] [PubMed] [Google Scholar]
  64. Whiteside T. L., Jost L. M., Herberman R. B. Tumor-infiltrating lymphocytes. Potential and limitations to their use for cancer therapy. Crit Rev Oncol Hematol. 1992 Jan;12(1):25–47. doi: 10.1016/1040-8428(92)90063-v. [DOI] [PubMed] [Google Scholar]
  65. Xun C., Brown S. A., Jennings C. D., Henslee-Downey P. J., Thompson J. S. Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice. Transplantation. 1993 Aug;56(2):409–417. doi: 10.1097/00007890-199308000-00031. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES