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Natural Killer Cells: Cell Biology and Research Applications | Cytologics

Natural killer cells, or NK cells, are a type of cytotoxic lymphocytes associated with the rapidly growing group of innate lymphoid cells (ILCs). They are an essential component of the innate immune system. They exhibit an immediate cytolytic response to the stressed cells, such as cancer cells and virus-infected cells.[1] In humans, they account for


Natural killer cells, or NK cells, are a type of cytotoxic lymphocytes associated with the rapidly growing group of innate lymphoid cells (ILCs). They are an essential component of the innate immune system. They exhibit an immediate cytolytic response to the stressed cells, such as cancer cells and virus-infected cells.[1] In humans, they account for 5 to 20% of all the circulating lymphocytes. They are also known as large granular lymphocytes.

Initially, natural killer cells were thought to originate from the bone marrow. However, recent studies have suggested that these innate immune cells can also develop and mature in secondary lymphoid tissues or SLTs, i.e., lymph nodes (LNs), tonsils and spleen, etc.[2]

Studies have shown that natural killer cells also cross-talk with other immune cells, which is imperative for stimulating both innate and adaptive immune reactions. When NK cells interact with eosinophils, they are activated, release IFNγ and enhance cytotoxic activity against multiple cellular targets.[3]

Subsets of Natural Killer Cells

Natural killer cells are divided into two main subtypes based on the cell surface density of CD56, i.e., CD56-bright and CD56-dim. Both subsets have distinct phenotypic and functional characteristics and play specific roles in immune responses.

CD56-bright subtype possesses a relatively low natural cytotoxicity and can abundantly produce cytokines, followed by monocytes activation. In contrast, CD56-dim is more cytotoxic. It represents high levels of immunoglobulin-like NK and CD16 receptors compared to the CD56-bright natural killer subset.[4]

Uses of NK Cells in Research

NK cells are known to have an inclusive antiviral and anti-tumor potential. Extensive research is being conducted to manipulate NK cells to develop highly effective and responsive cell-based immune therapies.

Cancer Immunotherapy

  • NK cells naturally tend to kill multiple adjacent cells that express cancer transformation-associated surface markers or oncogenic antigens. Therefore, they are becoming imperative for targeted molecular therapies against several cancer types. Many natural killer cells are modified to enhance their clinical activity, such as chimeric antigen receptor (CAR) NK cells.[5]
  • CAR-NK cells are being engineered to achieve effective anti-cancer response by targeting multiple antigens, enhancing penetration into solid tumors, and managing tumor microenvironment resistance. They have unrestricted proliferation ability and perseverance, thus offering significant advantages, including higher feasibility, improved safety, and several mechanisms for cytotoxic response activation.[6]
  • A recent study engineered natural killer cells anchored with nucleic acid aptamers and explored their anti-tumor effect against triple-negative breast cancer (TNBC). Aptamers are ligands that have a high binding affinity for their targets. These aptamer-engineered NK cells effectively induced the death of breast cancer cells only with a bit of effect on normal cells in the vicinity. Moreover, targeted immunotherapy via these NK cells restricted lung metastasis of triple-negative breast cancer cells.[7]

Antiviral Activity

  • Natural killer cells are considered an efficient therapy to inhibit human immunodeficiency virus infection. However, research is being conducted to evaluate their role in eliminating the pool of latently infected cells, as HIV can bounce back after the termination of anti-retroviral treatment. Such as, a recent study has used human peripheral blood NK cells in combination with other therapies, i.e., latency-reversing agents and protein kinase C modulator, to develop a kick and kill strategy. This approach noticeably reduced the viral bounce back. Moreover, it successfully eradicated the HIV reservoir in the animal model during the therapy, thus proposing an effective HIV treatment option.[8]
  • Previous research has shown a promising antiviral response of NK cell therapies in virus-infected individuals. NK cell exhaustion and low levels can contribute to the severity of viral infections. Thus, the administration of healthy and efficient natural killer cells, i.e., DVX201, into SARS CoV-2 affected patients can help alleviate the condition and restrict disease progression.[9]

Role in Reproduction and Recurrent Miscarriages

  • The characteristic role of NK cells is not clearly understood in human reproduction. However, studies have shown their physiological role during pregnancy. High levels of natural killer cells are linked to recurrent miscarriages therefore, they have been extensively investigated in this context. A recent study has observed that women with recurrent miscarriages have functionally more active and high proinflammatory cytokines producing natural killer cells compared to the control women.[10] Further mechanisms need to be elucidated to understand whether this effect is limited to only decidual NK cells or is also a result of high circulating NK cells.


Natural killer cells are a critical component of innate immunity responsible for mounting an immune response against virus-infected cells and tumor cells.

This article provided a brief explanation of the primary function and underlying processes regulating NK cells. New discoveries are made almost daily that are expanding our knowledge of the role NK cells play in immunity, including the treatment of cancer and other diseases.

If you’re interested in learning more on this topic, then check out some of our recent blog posts on research involving NK cells and the development of new immunotherapies.

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[1] Paul, S. and G. Lal, The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Frontiers in immunology, 2017. 8: p.1124.

[2] Abel, A.M., et al., Natural killer cells: development, maturation, and clinical utilization. Frontiers in immunology, 2018. 9: p. 1869.

[3] Pesce, S., et al., The innate immune cross-talk between NK cells and eosinophils is regulated by the interaction of natural cytotoxicity receptors with eosinophil surface ligands. Frontiers in immunology, 2017. 8: p. 510.

[4] Cooper, M.A., T.A. Fehniger, and M.A. Caligiuri, The biology of human natural killer-cell subsets. Trends in immunology, 2001. 22(11): p. 633-640.

[5] Shimasaki, N., A. Jain, and D. Campana, NK cells for cancer immunotherapy. Nature reviews Drug discovery, 2020. 19(3): p. 200-218.

[6] Xie, G., et al., CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine, 2020. 59: p. 102975.

[7] Chen, Z., et al., Targeted immunotherapy of triple-negative breast cancer by aptamer-engineered NK cells. Biomaterials, 2022. 280: p. 121259.

[8] Kim, J.T., et al., Latency reversal plus natural killer cells diminish HIV reservoir in vivo. Nature Communications, 2022. 13(1): p. 1-14.

[9] Jeyaraman, M., et al., Bracing NK cell-based therapy to relegate pulmonary inflammation in COVID-19. Heliyon, 2021. 7(7): p. e07635.

[10] Guerrero, B., et al., Natural killer cells in recurrent miscarriage: An overview. Journal of Reproductive Immunology, 2020. 142: p. 103209.

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