Original article| Volume 102, ISSUE 4, P577-589, October 1983

Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency

  • John I. Allen
    Reprint requests: John I. Allen, M.D., Gastroenterology Section (111D), VA Medical Center, 54th St. & 48th Avenue South, Minneapolis, Minn. 55417.
    From the Department of Medicine, Sections of Gastroenterology and Hematology, Veterans Administration Medical Center, Minneapolis, Minn., USA
    Search for articles by this author
  • Robert T. Perri
    From the Department of Medicine, Sections of Gastroenterology and Hematology, Veterans Administration Medical Center, Minneapolis, Minn., USA
    Search for articles by this author
  • Craig J. McClain
    From the Department of Medicine, Sections of Gastroenterology and Hematology, Veterans Administration Medical Center, Minneapolis, Minn., USA
    Search for articles by this author
  • Neil E. Kay
    From the Department of Medicine, Sections of Gastroenterology and Hematology, Veterans Administration Medical Center, Minneapolis, Minn., USA
    Search for articles by this author
      This paper is only available as a PDF. To read, Please Download here.


      Zinc deficiency alters lymphocyte and monocyte function in man and animals. A patient with isolated zinc deficiency was found to have lymphopenia (420 lymphocytes/μl), depressed T-cell mitogen response (48% of normal control), increased numbers of circulating T-suppressor cells (OKT8 reactive cells) and decreased circulating T-helper cells (OKT4 reactive cells). Activity of the patient's natural killer (NK) cells was 1 lytic unit/106 cells (normal 10 to 40), and monocyte cytotoxicity (MC) was four times that of normal controls. Zinc repletion in vivo improved the peripheral lymphocyte count, corrected the abnormal OKT8-to-OKT4 ratio, normalized T-cell response to mitogen, improved NK function, and lowered MC to control values. A divalent cation chelator, 1,10-orthophenanthroline (OP), was used to simulate zinc deficiency in vitro. T-cells exposed to OP are nonresponsive to mitogen unless zinc is added. NK function of lymphocytes from normal donors exposed to OP was depressed in a time- and dose-dependent manner. NK activity of peripheral blood lymphocytes (PBL) from 12 normal donors exposed to 50 μM OP for 16 hr was 10.3 ± 7 lytic units/106 cells (mean ± S.E.M.) vs. 32.6 ± 14 for cells incubated in medium alone. When monocytes were exposed for 16 hr to 50 μM OP, however, MC significantly increased to a range two to five times that of control. OP-induced alterations of lymphocyte and monocyte function was reversed by the addition of 50 μM zinc but not calcium or magnesium. Since NK activity and MC are thought to be important in host tumor immunity, alterations in zinc metabolism may have important implications for human tumor immune surveillance mechanisms.


      natural killer cell ((NK)), sheep erythrocyte rosetting ((ER)), monocyte cytotoxicity ((MC)), 110-orthophenanthroline ((OP)), phytohemagglutinin ((PHA)), RPMI with 10% fetal calf serum ((RPMI-FCS)), RPMI with 10% human Type AB serum ((RPMI-AB)), RPMI with 20% autologous serum ((RPMI-AS)), RPMI-AB with trypticase soy broth ((RPMI-ABTryp)), peripheral blood lymphocytes ((PBL)), phosphate-buffered saline ((PBS)), lytic unit(s) ((LU)), ethylenediaminetetraacetate ((EDTA))
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Good RA
        Nutrition and immunity.
        J Clin Immunol. 1981; 1: 3
        • Falchuk KH
        • Krishan A
        1,10-Phenanthroline inhibition of lymphoblast cell cycle.
        Cancer Res. 1977; 37: 2050
        • Chvapil M
        Effect of zinc on cells and biomembranes.
        Med Clin North Am. 1976; 60: 799
        • Underwood ET
        Trace Elements in Human Animal Nutrition.
        in: Academic Press, Inc, New York1971: 208
        • Frost P
        • Chen JC
        • Rabbani I
        • Smith J
        • Prasad AS
        The effect of zinc deficiency on the immune response.
        in: Zinc Metabolism: Current Aspects in Health and Disease. Alan R. Liss, Inc, New York1977: 143
        • Fernandes G
        • Nair M
        • Onoe K
        • Tanaka T
        • Floyd R
        • Good RA
        Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice.
        in: ed. 3. Proc Natl Acad Sci USA. 76. 1979: 457
        • Luecke RW
        • Simonel CE
        • Fraker PJ
        The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse.
        J Nutr. 1978; 108: 881
        • Oleske JM
        • Westphal ML
        • Shore S
        • Gorden D
        • Bogden JD
        • Nahmias A
        Zinc therapy of depressed cellular immunity in acrodermatitis enteropathica.
        Am J Dis Child. 1979; 133: 915
        • Miller ER
        • Luecke RW
        • Ullrey DE
        • Baltzer BV
        • Bradley BL
        • Hoefer JA
        Biochemical, skeletal and allometric changes due to zinc deficiency in the baby pig.
        J Nutr. 1968; 95: 278
        • Brummerstedt E
        • Flatstad T
        • Basse A
        • Andresen E
        The effect of zinc on calves with hereditary thymus hypoplasia (Lethal Trait A 46).
        Acta Pathol Microbiol Scand [A]. 1971; 79: 686
        • Beach RS
        • Gershwin ME
        • Hurley LS
        Altered thymic structure and mitogen responsiveness in postnatally zinc-deprived mice.
        Dev Comp Immunol. 1979; 3: 725
        • Iwata T
        • Incefy GS
        • Tanaka T
        • Fernandes G
        • Menendez-Botet CJ
        • Pih K
        • Good RA
        Circulating thymic hormone levels in zinc deficiency.
        Cell Immunol. 1979; 47: 100
        • Fraker PJ
        • DePasquale-Jardieu P
        • Zwicki CM
        • Luecke RW
        Regeneration of T-cell helper function in zinc-deficient adult mice.
        in: ed. 3. Proc Natl Acad Sci USA. 75. 1978: 5660
        • Frost P
        • Rabbani P
        • Smith J
        • Prasad A
        Cell-mediated cytotoxicity and tumor growth in zinc-deficient mice.
        in: ed. 3. Proc Soc Exp Biol Med. 167. 1981: 333
        • Chandra RK
        • Au B
        Single nutrient deficiency and cell-mediated immune responses.
        Am J Clin Nutr. 1980; 33: 736
        • Weston WL
        • Hutt JC
        • Humbert JR
        • Hambidge KM
        • Neldner KH
        • Walravens PA
        Zinc correction of defective chemotaxis in acrodermatitis enteropathica.
        Arch Dermatol. 1977; 113: 422
        • Allen JI
        • Kay NE
        • McClain CJ
        Severe zinc deficiency in humans: association with a reversible T-lymphocyte dysfunction.
        Ann Intern Med. 1981; 95: 154
        • Pekarek RS
        • Sandstead HH
        • Jacob RA
        • Barcome DF
        Abnormal cellular immune responses during acquired zinc deficiency.
        Am J Clin Nutr. 1979; 32: 1466
        • Ruhl H
        • Kirchner H
        • Bochert G
        Kinetics of the Zn2+-stimulation of human peripheral lymphocytes in vitro.
        in: ed. 3. Proc Soc Exp Biol Med. 137. 1971: 1089
        • Duchateau J
        • Delespesse G
        • Vereecke P
        Influence of oral zinc supplementation on the lymphocyte response to mitogens of normal subjects.
        Am J Clin Nutr. 1981; 34: 88
        • Chvapil M
        • Stankova L
        • Bernhard DS
        • Weldy PL
        • Carlson EC
        • Campbell JB
        Effect of zinc on peritoneal macrophages in vitro.
        Infect Immun. 1977; 16: 367
        • Karl L
        • Chvapil M
        • Zukoski CE
        Effect of zinc on the viability and phagocytic capacity of peritoneal macrophages.
        in: ed. 3. Proc Soc Exp Biol Med. 142. 1973: 1123
        • Williams RO
        • Loeb LA
        Zinc requirement for DNA replication in stimulated human lymphocytes.
        J Cell Biol. 1973; 58: 594
        • Krishnamurti C
        • Saryan LA
        • Petering DH
        Effects of ethylenediaminetetraacetic acid and 1,10-phenanthroline on cell proliferation and DNA synthesis of Ehrlich ascites cells.
        Cancer Res. 1980; 40: 4092
        • Brada Z
        • Bulba S
        Influence of 1,10-phenanthroline on liver tumorigenesis.
        Res Commun Chem Pathol Pharmacol. 1972; 3: 383
        • McClain CJ
        • Soutor C
        • Steele N
        • Levine AS
        • Silvis SE
        Severe zinc deficiency presenting with acrodermatitis during hyperalimentation: diagnosis, pathogenesis and treatment.
        J Clin Gastroenterol. 1980; 2: 1125
        • Koren HS
        • Anderson SJ
        • Fischer DG
        • Copeland CS
        • Jensen PJ
        Regulation of human natural killing. I. The role of monocytes, interferon and prostaglandins.
        J Immunol. 1981; 127: 2007
        • West WH
        • Cannon GB
        • Kay HD
        • Bonnard GD
        • Herberman RB
        Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells.
        J Immunol. 1977; 118: 355
        • Rosenberg EB
        • McCoy JL
        • Green SS
        • Donnelly FC
        • Siwarski D
        • Levine PH
        • Herberman RB
        Destruction of human lymphoid tissue culture cell lines by human peripheral blood lymphocytes in 51Cr release cellular cytotoxicity.
        JNCI. 1974; 52: 345
        • Lozzio BB
        • Lozzio CB
        • Bamberger EG
        • Fella AS
        A multipotential leukemia cell line (K562) of human origin.
        in: ed. 3. Proc Soc Exp Biol Med. 166. 1981: 546
        • Rinehart JJ
        • Lange P
        • Gormus BJ
        • Kaplan ME
        Human monocyte-induced tumor cell cytotoxicity.
        Blood. 1978; 52: 211
        • LeMarbre P
        • Rinehart JJ
        • Kay NE
        • Vesella R
        • Jacob HS
        Lysozyme enhances monocytemediated tumoricidal activity: a potential amplifying mechanism of tumor killing.
        Blood. 1981; 58: 994
        • Douglas SD
        Electron microscopic and functional aspects of human lymphocyte response to mitogens.
        Transplant Rev. 1972; 11: 39
        • Levin J
        • Tomasulo PA
        • Oser RS
        Detection of endotoxin in human blood and demonstration of an inhibitor.
        J Lab Clin Med. 1970; 75: 903
        • Thomas Y
        • Sosman J
        • Irigoyen O
        • Friedman SM
        • Kung PC
        • Goldstein G
        • Chess L
        Functional analysis of human T-cell subsets defined by monoclonal antibodies. I. Collaborative T-T interactions in the immunoregulation of B cell differentiation.
        J Immunol. 1980; 125: 2402
        • Reinherz EL
        • Kung PC
        • Goldstein G
        • Schlossman SF
        Separation of functional subsets of human T cells by a monoclonal antibody.
        in: ed. 3. Proc Natl Acad Sci USA. 76. 1979: 4061
        • Bates J
        • McClain CJ
        The effect of severe zinc deficiency on serum levels of albumin, transferrin and prealbumin in man.
        Am J Clin Nutr. 1981; 34: 1655
        • Burgert SL
        • Anderson CF
        An evaluation of upper arm measurements used in nutritional assessment.
        Am J Clin Nutr. 1979; 32: 2136
        • Jeejeebhoy KN
        • Chu RC
        • Marliss EB
        • et al.
        Chromium deficiency, glucose intolerance and neuropathy reversed by chromium supplementation in a patient receiving long-term total parenteral nutrition.
        Am J Clin Nutr. 1977; 30: 531
        • VanRij AM
        • Thomson CD
        • McKenzie JM
        • et al.
        Selenium deficiency in total parenteral nutrition.
        Am J Clin Nutr. 1979; 32: 2076
        • Solomons NW
        On the assessment of zinc and copper nutriture in man.
        Am J Clin Nutr. 1979; 32: 856
        • Brummerstedt E
        • Andresen E
        • Basse A
        • Flagstad T
        Lethal strain A 46 in cattle. Immunological investigations.
        Nord Vet Med. 1974; 26: 279
        • Flynn A
        • Yen BR
        Mineral deficiency effects on the generation of cytotoxic T-cells and T-helper cell factors in vitro.
        J Nutr. 1981; 111: 907
        • Zanzonico P
        • Fernandes G
        • Good RA
        The differential sensitivity of T-cell and T-cell mitogenesis to in vitro zinc deficiency.
        Cell Immunol. 1981; 60: 203
        • Berger NA
        • Johnson ES
        • Skinner M
        Ortho-phenanthroline inhibition of DNA synthesis in mammalian cells.
        Exp Cell Res. 1975; 96: 145
        • Chang C-H
        • Yarbro JW
        • Mann Jr, DE
        • Gautieri RF
        Effects of 1,10-phenanthroline and a zinc complex of 1,10-phenanthroline on nucleic acid synthesis in mouse liver and spleen.
        J Pharmacol Exp Ther. 1978; 205: 27
        • Minkel DT
        • Dolhun PJ
        • Calhoun BL
        • Saryan LA
        • Petering DH
        Zinc deficiency and growth or Ehrlich ascites tumor.
        Cancer Res. 1979; 39: 2451
        • D'Aurora V
        • Stern AM
        • Sigman DS
        Inhibition of E. coli DNA polymerase I by 1,10-phenanthroline.
        Biochem Biophys Res Commun. 1977; 78: 170
        • Downey KM
        • Que BG
        • So AG
        Degradation of DNA by 1,10-phenanthroline.
        Biochem Biophys Res Commun. 1980; 93: 264
        • Herberman RB
        • Holden HT
        Natural cell-mediated immunity.
        Adv Cancer Res. 1978; 27: 305
      1. Herberman RB Natural Cell-mediated Immunity Against Tumors. Academic Press, Inc, New York1980
        • Reynolds CW
        • Timonen T
        • Herberman RB
        Natural killer (NK) cell activity in the rat. I. Isolation and characterization of the effector cells.
        J Immunol. 1981; 127: 282
        • Hanna N
        Expression of metastatic potential of tumor cells in young nude mice is correlated with low levels of natural killer cell-mediated cytotoxicity.
        Int J Cancer. 1980; 26: 675
        • Haliotis T
        • Roder J
        • Klein M
        • Ortaldo J
        • Fauci AS
        • Herberman RB
        Chediak-Higashi gene in humans. I. Impairment of natural killer function.
        J Exp Med. 1980; 151: 1039
        • Behelak Y
        • Banerjee D
        • Richter M
        Immunocompetent cells in patients with malignant disease. I. The lack of naturally occurring killer cell activity in the unfractionated circulating lymphocytes from patients with chronic lymphocytic leukemia.
        Cancer. 1976; 38: 2274
        • Minato N
        • Takedo A
        • Kano S
        • Takaka F
        Studies of the functions of natural killer-interferon system in patients with Sjogren syndrome.
        J Clin Invest. 1982; 69: 581
        • Goto M
        • Tanimot K
        • Horiuchi Y
        Natural cell-mediated cytotoxicity in systemic lupus erythematosus: suppression by antilymphocyte antibody.
        Arthritis Rheum. 1980; 23: 1274
        • Takasugi M
        • Ramseyer A
        • Takasugi J
        Decline of natural nonselective cell-mediated autotoxicity in patients with tumor progression.
        Cancer Res. 1977; 37: 413
        • Lemarbre P
        • Hoidal J
        • Vesella R
        • Rinehart J
        Human pulmonary macrophage tumor cell cytotoxicity.
        Blood. 1980; 55: 612
        • Kelinerman ES
        • Zwelling LA
        • Howser D
        • Barlock A
        • Young RC
        • Decker JM
        • Bull J
        • Muchmore AV
        Defective monocyte killing in patients with malignancies and restoration of function during chemotherapy.
        Lancet. 1980; 2: 1102
        • Nelson DJ
        • Kiremidjian-Schumacher L
        • Stotzky G
        Effects of cadium, lead and zinc on macrophage-mediated cytotoxicity toward tumor cells.
        Environ Res. 1982; 28: 154