Medical Policies - Medicine

Natural Killer (NK) Cells


Effective Date:10-01-2018



Measurement of natural killer (NK) cells is considered experimental, investigational and/or unproven for any indication.


The organs of the immune system, called lymphoid organs, work together to clear infection from the body. Lymphoid organs include lymph nodes, lymphatic vessels, and lymphocytes (white blood cells), as well as the spleen, bone marrow, tonsils, adenoids, and thymus gland. There are two major classes of lymphocytes: B cells and T cells. B cells grow to maturity in the bone marrow, and produce antibodies that attach to foreign antigens, marking them for destruction by other immune cells; this is the antibody-mediated response, or humoral immunity. T cells mature in the thymus gland. They attack and destroy diseased cells that they recognize as foreign, as well as regulate and coordinate the overall immune response; this is cell-mediated response, or cellular immunity.

Natural killer (NK) cells are a type of lymphocyte that provide the first line of defense against pathogens by containing infections while the adaptive immune response is generating antigen specific cytotoxic T cells that can clear the infection. NK cells target a wide variety of infectious microbes, tumor cells, and other abnormal cells; they do not need to recognize a specific antigen before they attack and destroy a target cell. Unlike phagocytes, they do not engulf and ingest target cells, but attach to them and inject chemicals that erode the membranes of the target cell and lead to cellular destruction.

The exact mechanism NK cells use to determine which cells to target is not certain; one theory involves recognition of “altered self.” Major histocompatibility complex (MHC) molecules are anchored in cell membranes, where they display short polypeptides to T cells, via the T cell receptor (TCRs). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc. By design of the MHC-TCR interaction, T cells should ignore “self” peptides while reacting appropriately to the foreign peptides. Foreign peptides that provoke an immune response are termed antigens. NK cells have two types of surface receptors, “activating receptors” and “inhibitory receptors.” The inhibitory receptors recognize MHC class I alleles, which could explain why NK cells kill cells with low levels of MHC class I molecules; this is known as “missing self” recognition.

Natural killer cell activity can be an important indicator of disease progression and patient prognosis, and may be involved in how the immune system relates to such conditions as infertility, cancer, HIV, leukemia, chronic fatigue syndrome, infections and other diseases.


Natural killer (NK) cell count has been studied in relation to a variety of conditions, including cancer, HIV, chronic fatigue syndrome, infections and other diseases.


One area of interest, the relationship between NK cells and reproductive failure is a controversial area in reproductive medicine. Vaquero et al. (2006) (1) conducted a study to propose a set of tests to clarify the diagnosis of repeated implantation failure in patients undergoing in vitro fertilization (IVF); they concluded that thyroid abnormalities, antiphospholipid antibodies, and increased NK levels are more prevalent in women experiencing IVF failure. However, regarding NK cells and reproductive failure, Rai et al. (2005) (2) contend that there is no scientific basis for NK testing in routine practice, and the use of immunosuppressant agents based on the results of such testing may be potentially harmful. Ghazeeri and Kutteh (2001) (3) noted that the roles alloimmunity and autoimmunity may play in reproductive failure, including recurrent pregnancy loss and failed IVF, have not been clearly established, and they concluded that large, well-constructed studies examining the benefit of immunological evaluation and treatment are needed before definite recommendations can be made.

Moffett and Shreeve in a 2015 article note that the evidence that targeting uNK (uterine NK) or peripheral blood NK cells assists women with recurrent pregnancy failure is lacking. (10)


Tratkiewicz and Szer (1990) (4) studied the loss of NK activity as an indicator of relapse in acute leukemia. They concluded that there was a marked reduction in NK activity in patients with active leukemia when compared with healthy controls, and that NK activity substantially improved in complete remission. All patients who relapsed had significantly reduced NK activity, which in some significantly preceded the time of relapse. Their data suggest that regular assessment of NK activity may be a useful diagnostic tool in patients with acute leukemia.

NK cells are a promising area of immunology and cancer research. Experiments are being done on mice to learn how NK cells cause the immune system to respond to cancer cells. Also, Takanami et al., (2001) (5) studied the prognostic value of NK cell infiltration in resected pulmonary adenocarcinoma, and concluded that NK cell infiltration may contribute to regulation of tumor progression, and can serve as a useful prognostic marker in overall and stage I pulmonary adenocarcinoma.

In a 2015 article by Karakhanova et al., tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot were the methods used to identify immunological parameters in 92 patients with pancreatic adenocarcinoma from the CapRI trial who did not show any benefit of interferon-α in addition to a 5-fluorouracil (5FU)-based treatment. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method. Results noted by the authors included, irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. The authors identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy. Conclusions reached by the authors included the following: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients. Limitations to this study include a small number of patients evaluated. (8)


NK cell activity has been evaluated for a variety of other prognostic and diagnostic uses. el-Sameea et al., (2004) (6) evaluated NK cells as diagnostic markers of early onset neonatal sepsis; they reported that their data raised the possibility that adding NK cell activity to the standard workup of critically ill patients with suspected sepsis could increase the diagnostic certainty and generate improved patient management. Wozniakowska-Gesicka et al. (2000) (7) studied the prognostic value of NK cells in monitoring the course of IFN-alpha (Interferon-alpha) therapy in children with chronic hepatitis and concluded that increased NK cells in these children may be determinant of IFN therapy.

Systemic Autoimmune Diseases

In an article from Carvajal et al. (2017), the authors considered the distribution of B, T and natural killer cells in the blood could be helpful in determining a precise diagnosis in autoimmune diseases. They note that despite the low number of studies, anomalies of lymphocyte subset distribution were also described in ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis, systemic scleroderma and myositis. For now, flow cytometric analysis of lymphocyte subsets has focused mainly on specific subpopulations and is more useful for basic and translational research than for diagnostics in clinical practice. (9)

Summary of Evidence

While measurement of NK cells may support certain diagnoses or conditions, specific studies are scattered, small, and inconclusive. Therefore, measurement of NK cells is not supported by evidence in the peer-reviewed medical literature that permits conclusions on the effect of NK cell measurement on health outcomes, or that demonstrates an improvement in net health outcome through use of NK cell measurement.


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Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

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1. Vaquero E, Lazzarin N, Caserta D, et al. Diagnostic evaluation of women experiencing repeated in vitro fertilization failure. Eur J Obstet Gyneco Reprod Biol. 2006 Mar 1; 125(1):79-84. PMID 16223559

2. Rai R, Sacks G, Trew G, et al. Natural killer cells and reproductive failure—theory, practice and prejudice. Hum Reprod. 2005 May; 20(5):1123-6. PMID 15760961

3. Ghazeeri GS, Kutteh WH Immunological testing and treatment in reproduction: frequency assessment of practice patterns at assisted reproduction clinics in the USA and Australia. Hum Reprod. 2001 October; 16(10):2130-5. PMID 11574504

4. Tratkiewicz, JA and Szer J. Loss of natural killer activity as an indicator of relapse in acute leukaemia. Clinical and Experimental Immunology. 1990 May; 80(2):241-6. PMID 2357852

5. Takanami L, Takeuchi K, Giga M. The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. J Thorac Cardiovasc Surg. 2001 Jun; 121(6):1058-63. PMID 11385371

6. el-Sameea ER, Metwally SS, Mashhour E, et al. Evaluation of natural killer cells as diagnostic markers of early onset neonatal sepsis: comparison with C-reactive protein and interleukin-8. Egypt J Immunol. 2004; 11(1):91-102. PMID 15724391

7. Wozniakowska-Gesicka T, Wisniewska-Ligier M, Zeman K, et al. Prognostic value of natural killer cells monitoring in the course of IFN-alpha therapy in children with chronic hepatitis C. Pol Merkur Lekarski. 2000 Jun; 8(48):376-7. PMID 10967910

8. Karakhanova S, Ryschich E, Mosl B, et al. Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma. Br J Cancer. 2015 Mar 17; 112(6):1027-36. PMID 25742476

9. Carvajal AG, Gazear P, Hillion S, et al. Could Lymphocyte Profiling be useful to Diagnose Systemic Autoimmune diseases? Clin Rev Allergy Immunol. 2017 Oct; 53(2):219-36. PMID 28474288

10. Moffett A and Shreeve N. First do no harm: uterine natural killer (NK) cells in assisted reproduction. Hum Reprod. 2015. Jul; 30(7):1519-25. PMID 25957039

11. The Immune Cells. National Institute of Allergy and Infectious Diseases. Available at: <> (accessed July 16, 2018).

12. Brandstadter J and Yang Y. Natural Killer Cell Responses to Viral Infection. J Innate Immun. 2011; 3(3):274-9. PMID 21411975

Policy History:

10/1/2018 Document updated with literature review. Coverage unchanged. References 9-12 added. Some references removed.
4/1/2017 Reviewed. No changes.
7/1/2016 Document updated with literature review. Coverage unchanged.
1/1/2015 Reviewed; no changes.
12/1/2013 Document updated with literature review. Coverage unchanged.
11/1/2010 Document updated with literature review. Coverage unchanged.
10/15/2008 Revised/updated entire document
12/1/2006 New Medical Document

Archived Document(s):

Title:Effective Date:End Date:
Natural Killer (NK) Cells04-01-201709-30-2018
Natural Killer (NK) Cells07-01-201603-31-2017
Natural Killer (NK) Cells01-01-201506-30-2016
Natural Killer (NK) Cells12-01-201312-31-2014
Natural Killer (NK) Cells11-01-201011-30-2013
Natural Killer (NK) Cells10-15-200810-31-2010
Natural Killer (NK) Cells12-01-200610-14-2008
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