How I Manage Natural Killer Cell Deficiency

  • Jordan S. OrangeEmail author
How I Manage


Natural killer (NK) cell deficiency (NKD) is a subset of primary immunodeficiency disorders (PID) in which an abnormality of NK cells represents a major immunological defect resulting in the patient’s clinical immunodeficiency. This is distinct from a much larger group of PIDs that include an NK cell abnormality as a minor component of the immunodeficiency. Patients with NKD most frequently have atypical consequences of herpesviral infections. There are now 6 genes that have been ascribed to causing NKD, some exclusively and others that also cause other known immunodeficiencies. This list has grown in recent years and as such the mechanistic and molecular clarity around what defines an NKD is an emerging and important field of research. Continued increased clarity will allow for more rational approaches to the patients themselves from a therapeutic standpoint. Having evaluated numerous individuals for NKD, I share my perspective on approaching the diagnosis and managing these patients.


NK cells natural killer cell deficiency primary immunodeficiency 



I would like to thank Dr. Emily Mace who has been my close collaborator in advancing the understanding of NKD and who provided thoughtful feedback on this manuscript. My effort towards this topic was supported by NIH-NIAID R01AI120989. I would also like to thank my colleagues who have indulged me with the opportunity to think about challenging patients with them as well as those who have been collaborators in NK cell-oriented investigation. Finally, I would like to thank the patients and families who have participated in our research efforts to try and understand more about NK cells in PID and human immune defenses.

Compliance with Ethical Standards

Conflict of Interest

The author declares the following potential conflicts of interest: Royalty received for authorship of Up To Date (Wolters Kluwer Publishing) chapters on NK cell deficiency, and fees received in consultation to manufacturers of therapeutic immunoglobulin ADMA biologics (scientific advisory board membership) and Takeda.


  1. 1.
    Lim AI, Di Santo JP. ILC-poiesis: ensuring tissue ILC differentiation at the right place and time. Eur J Immunol. 2019;49(1):11–8. Scholar
  2. 2.
    Orange JS, Mace EM, French AR, Yokoyama WM, Fehniger TA, Cooper MA. Comment on: evidence of innate lymphoid cell redundancy in humans. Nat Immunol. 2018;19(8):788–9. Scholar
  3. 3.
    Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10. Scholar
  4. 4.
    Ali A, Gyurova IE, Waggoner SN. Mutually assured destruction: the cold war between viruses and natural killer cells. Curr Opin Virol. 2019;34:130–9. Scholar
  5. 5.
    Malmberg KJ, Carlsten M, Bjorklund A, Sohlberg E, Bryceson YT, Ljunggren HG. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol. 2017;31:20–9. Scholar
  6. 6.
    Sojka DK, Yang L, Yokoyama WM. Uterine natural killer cells: to protect and to nurture. Birth Defects Res. 2018;110(20):1531–8. Scholar
  7. 7.
    Angelo LS, Banerjee PP, Monaco-Shawver L, Rosen JB, Makedonas G, Forbes LR, et al. Practical NK cell phenotyping and variability in healthy adults. Immunol Res. 2015;62(3):341–56. Scholar
  8. 8.
    Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity. 2017;47(5):820–33. Scholar
  9. 9.
    Geary CD, Sun JC. Memory responses of natural killer cells. Semin Immunol. 2017;31:11–9. Scholar
  10. 10.
    Sivori S, Vacca P, Del Zotto G, Munari E, Mingari MC, Moretta L. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications. Cell Mol Immunol. 2019;16(5):430–41. Scholar
  11. 11.
    Rajalingam R. Diversity of killer cell immunoglobulin-like receptors and disease. Clin Lab Med. 2018;38(4):637–53. Scholar
  12. 12.
    Vitale M, Cantoni C, Della Chiesa M, Ferlazzo G, Carlomagno S, Pende D, et al. An historical overview: the discovery of how NK cells can kill enemies, recruit defense troops, and more. Front Immunol. 2019;10:1415. Scholar
  13. 13.
    Orange JS, Fassett MS, Koopman LA, Boyson JE, Strominger JL. Viral evasion of natural killer cells. Nat Immunol. 2002;3(11):1006–12. Scholar
  14. 14.
    Jonjic S, Babic M, Polic B, Krmpotic A. Immune evasion of natural killer cells by viruses. Curr Opin Immunol. 2008;20(1):30–8. Scholar
  15. 15.
    Martinez-Vicente P, Farre D, Sanchez C, Alcami A, Engel P, Angulo A. Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor. PLoS Pathog. 2019;15(4):e1007658. Scholar
  16. 16.
    Mace EM, Dongre P, Hsu HT, Sinha P, James AM, Mann SS, et al. Cell biological steps and checkpoints in accessing NK cell cytotoxicity. Immunol Cell Biol. 2014;92(3):245–55. Scholar
  17. 17.
    Gwalani LA, Orange JS. Single degranulations in NK cells can mediate target cell killing. J Immunol. 2018;200(9):3231–43. Scholar
  18. 18.
    Orange JS. Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol. 2008;8(9):713–25. Scholar
  19. 19.
    Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20–6. Scholar
  20. 20.
    Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 2018;132(1):89–100. Scholar
  21. 21.
    Huntington ND. The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunol Cell Biol. 2014;92(3):210–3. Scholar
  22. 22.
    Ham H, Billadeau DD. Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity. Front Immunol. 2014;5:2. Scholar
  23. 23.
    Mace EM, Orange JS. Emerging insights into human health and NK cell biology from the study of NK cell deficiencies. Immunol Rev. 2019;287(1):202–25. Scholar
  24. 24.
    Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002;4(15):1545–58.CrossRefGoogle Scholar
  25. 25.
    Orange JS. NK cell deficiency syndromes. In: Rose B, (ed) UpToDate. Waltham 2018.
  26. 26.
    Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013;132(3):515–25. Scholar
  27. 27.
    Voss M, Bryceson YT. Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans. Clin Immunol. 2017;177:29–42. Scholar
  28. 28.
    Mace EM. Requirements for human natural killer cell development informed by primary immunodeficiency. Curr Opin Allergy Clin Immunol. 2016;16(6):541–8. Scholar
  29. 29.
    Orange JS. Natural killer cell deficiency. In: Sullivan KE, Stiehm ER, editors. Stiehm’s immune deficiencies. London: Elsevier/AP; 2014. p. 765–72.CrossRefGoogle Scholar
  30. 30.
    Mace EM, Hsu AP, Monaco-Shawver L, Makedonas G, Rosen JB, Dropulic L, et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood. 2013;121(14):2669–77. Scholar
  31. 31.
    Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–21. Scholar
  32. 32.
    Cottineau J, Kottemann MC, Lach FP, Kang YH, Vely F, Deenick EK, et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest. 2017;127(5):1991–2006. Scholar
  33. 33.
    Mace EM, Bigley V, Gunesch JT, Chinn IK, Angelo LS, Care MA, et al. Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest. 2017;127(1):306–20. Scholar
  34. 34.
    Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012;122(3):821–32. Scholar
  35. 35.
    Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, et al. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012;122(3):814–20. Scholar
  36. 36.
    Hanna S, Beziat V, Jouanguy E, Casanova JL, Etzioni A. A homozygous mutation of RTEL1 in a child presenting with an apparently isolated natural killer cell deficiency. J Allergy Clin Immunol. 2015;136(4):1113–4. Scholar
  37. 37.
    Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, et al. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012;122(10):3769–80. Scholar
  38. 38.
    Jawahar S, Moody C, Chan M, Finberg R, Geha R, Chatila T. Natural killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin Exp Immunol. 1996;103(3):408–13.CrossRefGoogle Scholar
  39. 39.
    Jouanguy E, Gineau L, Cottineau J, Beziat V, Vivier E, Casanova JL. Inborn errors of the development of human natural killer cells. Curr Opin Allergy Clin Immunol. 2013;13(6):589–95. Scholar
  40. 40.
    Mace EM, Orange JS. Genetic causes of human NK cell deficiency and their effect on NK cell subsets. Front Immunol. 2016;7:545. Scholar
  41. 41.
    Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med. 1989;320(26):1731–5.CrossRefGoogle Scholar
  42. 42.
    Eidenschenk C, Dunne J, Jouanguy E, Fourlinnie C, Gineau L, Bacq D, et al. A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am J Hum Genet. 2006;78(4):721–7.CrossRefGoogle Scholar
  43. 43.
    Etzioni A, Eidenschenk C, Katz R, Beck R, Casanova JL, Pollack S. Fatal varicella associated with selective natural killer cell deficiency. J Pediatr. 2005;146(3):423–5.CrossRefGoogle Scholar
  44. 44.
    Bernard F, Picard C, Cormier-Daire V, Eidenschenk C, Pinto G, Bustamante JC, et al. A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells. Pediatrics. 2004;113(1 Pt 1):136–41.CrossRefGoogle Scholar
  45. 45.
    Eidenschenk C, Jouanguy E, Alcais A, Mention JJ, Pasquier B, Fleckenstein IM, et al. Familial NK cell deficiency associated with impaired IL-2- and IL-15-dependent survival of lymphocytes. J Immunol. 2006;177(12):8835–43. Scholar
  46. 46.
    Fleisher G, Starr S, Koven N, Kamiya H, Douglas SD, Henle W. A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. J Pediatr. 1982;100(5):727–30. Scholar
  47. 47.
    Moon WY, Powis SJ. Does natural killer cell deficiency (NKD) increase the risk of cancer? NKD may increase the risk of some virus induced cancer. Front Immunol. 2019;10:1703. Scholar
  48. 48.
    Orange JS, Ramesh N, Remold-O’Donnell E, Sasahara Y, Koopman L, Byrne M, et al. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A. 2002;99(17):11351–6. Scholar
  49. 49.
    Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125(6 Pt 1):876–85. Scholar
  50. 50.
    Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5(10):617–25. Scholar
  51. 51.
    Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun. 2001;15(3):199–226. Scholar
  52. 52.
    Goyos A, Fort M, Sharma A, Lebrec H. Current concepts in natural killer cell biology and application to drug safety assessments. Toxicol Sci. 2019. Scholar
  53. 53.
    Cederbrant K, Marcusson-Stahl M, Condevaux F, Descotes J. NK-cell activity in immunotoxicity drug evaluation. Toxicology. 2003;185(3):241–50.CrossRefGoogle Scholar
  54. 54.
    Alsweed A, Alsuhibani M, Casanova JL, Al-Hajjar S. Approach to recurrent herpes simplex encephalitis in children. Int J Pediatr Adolesc Med. 2018;5(2):35–8. Scholar
  55. 55.
    Mahapatra S, Mace EM, Minard CG, Forbes LR, Vargas-Hernandez A, Duryea TK, et al. High-resolution phenotyping identifies NK cell subsets that distinguish healthy children from adults. PLoS One. 2017;12(8):e0181134. Scholar
  56. 56.
    Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129(9):1082–94. Scholar
  57. 57.
    Rubin TS, Zhang K, Gifford C, Lane A, Choo S, Bleesing JJ, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017;129(22):2993–9. Scholar
  58. 58.
    Gotlieb N, Rosenne E, Matzner P, Shaashua L, Sorski L, Ben-Eliyahu S. The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity. Brain Behav Immun. 2015;45:277–86. Scholar
  59. 59.
    Shaw RK, Issekutz AC, Fraser R, Schmit P, Morash B, Monaco-Shawver L, et al. Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency. Blood. 2012;119(17):4009–12. Scholar
  60. 60.
    Cohen JI. GATA2 Deficiency and Epstein-Barr virus disease. Front Immunol. 2017;8:1869. Scholar
  61. 61.
    Santoli D, Trinchieri G, Koprowski H. Cell-mediated cytotoxicity against virus-infected target cells in humans. II. Interferon induction and activation of natural killer cells. J Immunol. 1978;121(2):532–8.PubMedGoogle Scholar
  62. 62.
    Bolay H, Karabudak R, Aybay C, Candemir H, Varli K, Imir T, et al. Alpha interferon treatment in myasthenia gravis: effects on natural killer cell activity. J Neuroimmunol. 1998;82(2):109–15.CrossRefGoogle Scholar
  63. 63.
    Evans A, Main E, Zier K, Ikegaki N, Tartaglione M, Kennett R, et al. The effects of gamma interferon on the natural killer and tumor cells of children with neuroblastoma. A preliminary report. Cancer. 1989;64(7):1383–7.CrossRefGoogle Scholar
  64. 64.
    Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehra J, London L, Perussia B. Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 1984;160(4):1147–69.CrossRefGoogle Scholar
  65. 65.
    Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993;91(1):123–32. Scholar
  66. 66.
    Jyonouchi S, Gwafila B, Gwalani LA, Ahmad M, Moertel C, Holbert C, et al. Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome. Clin Immunol. 2017;179:47–53. Scholar
  67. 67.
    Notarangelo LD, Mazzolari E. Natural killer cell deficiencies and severe varicella infection. J Pediatr. 2006;148(4):563–4 author reply 4.CrossRefGoogle Scholar
  68. 68.
    Naik S, Nicholas SK, Martinez CA, Leen AM, Hanley PJ, Gottschalk SM, et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol. 2016;137(5):1498–505 e1. Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, NewYork Presbyterian Morgan Stanley Children’s HospitalColumbia University Vagelos College of Physicians and SurgeonsNew YorkUSA

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