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Natural Killer Cells: NK Cell Origin, Function and Related Conditions

Five natural killer cells attacking a tumor cell.
Credit: iStock.
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While some systems and cell types in the human body are well understood, there are still many mysteries and details to be discovered in respect to the immune system. Our knowledge of many immune cell types is still in flux. One such group are natural killer cells (NK cells), where recent findings have led to revisions in our understanding of the subpopulations and functions of this important cell type.

In this article, we consider what NK cells are, how they are generated, their function in the body and conditions related to them.

What are NK cells?

NK cells are a type of lymphocyte and a component of the innate immune system tasked with removing tumor cells and virus-infected cells from our bodies. Additionally, they play a role in the adaptive immune response by producing immune-modulating cytokines and also have some homeostatic functions. The term “natural killer” cell was first used by Rolf Kiessling and Hans Wigzell in 19751 when they observed that certain lymphocytes had the ability to kill tumor cells without prior sensitization by antigens. They were the first member of what are now called the innate lymphoid cells (ILC) of which there are three subsets (ILC1, ILC2 and ILC3).2 ILCs lack antigen-specific receptors like T cells and B cells, distinguishing them from adaptive immune lymphoid cells, and NK cells are a subset of the ILC1 lineage. About 5-15% of peripheral blood lymphocytes are NK cells. Nevertheless, they are also found in the liver, spleen, lungs, uterus, thymus and mucosal lymphoid tissues in varying numbers.3 NK cells are typically oval or round in shape with a large nucleus and a small cytoplasmic space with granules containing effector substances like perforin and granzymes.

As with other immune cells, they start life as a common hematopoietic stem cell, which then differentiates into a common lymphoid progenitor (CLP) cell4 and subsequently, through various intermediaries, into a mature NK cell (Figure 1).3 Transcription factors ID2 and E4BP4, and interleukin-2 (IL-2) and IL-15 cytokines have been implicated in the development, homeostasis and function of NK cells.5,6 This development occurs primarily in the bone marrow, but there is evidence that activation and maturation may occur in other sites as well.Flow diagram showing the differentiation pathway for the development of NK cells with the other related cell types indicated.

Figure 1: Diagram showing the differentiation pathway for the development of NK cells. Credit: Technology Networks.

Natural killer cell function

As a component of the innate immune system, NK cells are capable of responding in a very rapid manner to infected cells or tumor cells without prior sensitization. In addition to these functions, recent research has shown that they also play an important regulatory and homeostatic role. NK cells are characterized as being CD56+CD3 and are further subdivided into CD56Dim and CD56Bright subpopulations, based on the expression of surface molecules, which have both functional and phenotypic differences (Figure 2). CD56Dim NK cells are considered to be the cytotoxic subset that releases granules containing perforin and granzymes and are highly efficient in killing target cells, such as infected cells or cancer cells. They express high levels of CD16, which is a receptor for the Fc portion of antibodies, and are particularly effective in mediating antibody-dependent cellular cytotoxicity (ADCC), where they recognize antibody-coated target cells. They are predominantly found in the peripheral blood and are constantly looking out for defective cells. CD56Bright NK cells are the cytokine-producing subset. They produce immunoregulatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), and regulate immune responses by modulating the activity of other immune cells such as dendritic cells, T lymphocytes and macrophages. This subset are predominantly found in the secondary lymphoid tissues.7 There is also increasing evidence that NK cells have the capacity to develop memory capability, which is classically associated with the adaptive immune system.8

NK cell types and their effector functions with key molecules indicated.

Figure 2: NK cell types and their effector functions. Credit: Technology Networks.

NK cell-related conditions

NK cell-related conditions are relatively rare and complex, often involving interactions between genetic, environmental and immunological factors. Let us consider some of the main NK cell disorders.

  1. Chediak-Higashi syndrome (CHS): CHS is a rare, autosomal recessive genetic disorder in the lysosomal trafficking regulator gene (LYST). The disease is characterized by easy bruising, oculocutaneous albinism and predisposition to bacterial infection. This disorder affects various cells, including NK cells.9

  2. Severe combined immunodeficiency (SCID): SCID represents a group of rare and severe life-threatening, autosomal recessive genetic disorders that result in a significant compromise of the immune system. Some forms of SCID can affect NK cell development and function along with other immune cells.10 Unless treated, typically by stem cell transplantation, SCID is normally fatal.

  3. Hyper IgM syndrome (HIGM): This group of primary immunodeficiency disorders, which are normally X-chromosome-linked, are characterized by decreased serum levels of IgG, IgA and IgE but normal or elevated levels of IgM. Some forms of HIGM are associated with NK cell dysfunction, affecting the immune response against certain infections.11

  4. NK cell deficiency: In rare cases, individuals may have a primary deficiency in NK cells, leading to an increased susceptibility to viral infections and in some cases, certain cancers. These conditions may be associated with genetic mutations affecting NK cell development (classical NK cell deficiency (CNKD)) or function (functional NK cell deficiency (FNKD)).12

  5. Aggressive NK cell leukemia (ANKL): This rare, lethal disease is a malignancy arising from the uncontrolled proliferation of NK cells. Patients may present with acute fever, constitutional symptoms (tiredness, malaise and weight loss), hemophagocytic syndrome, hepatosplenomegaly and disseminated intravascular coagulation. In some cases, it has been linked with infection with Epstein-Barr virus.13

Historically, NK cells were considered only as being a component of the innate immune response, tasked with detecting and removing cancerous or virus-infected cells. However, recent research has shown that they are far more involved in the body’s whole immune response, interacting with a number of other cell types, eliciting regulatory and homeostatic functions.

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2.     Spits H, Artis D, Colonna M et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol. 2013 Feb;13(2):145-9. doi:10.1038/nri3365

3.     Yu J, Freud AG, Caligiuri MA. Location and cellular stages of natural killer cell development. Trends Immunol. 2013 Dec;34(12):573-82. doi:10.1016/j.it.2013.07.005

4.     Blom B, Spits H. Development of human lymphoid cells. Annu Rev Immunol. 2006;24:287-320. doi:10.1146/annurev.immunol.24.021605.090612

5.     Becknell B, Caligiuri MA. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol. 2005;86:209-39. doi:10.1016/S0065-2776(04)86006-1

6.     Pfefferle A, Jacobs B, Haroun-Izquierdo A, Kveberg L, Sohlberg E, Malmberg KJ. Deciphering natural killer cell homeostasis. Front Immunol. 2020 May 12;11:812. doi:10.3389/fimmu.2020.00812

7.     Vivier, E., Tomasello, E., Baratin, M. et al. Functions of natural killer cells. Nat Immunol 9, 2008, 503–510. doi:10.1038/ni1582

8.     O'Sullivan TE, Sun JC, Lanier LL. Natural killer cell memory. Immunity. 2015 Oct 20;43(4):634-45. doi:10.1016/j.immuni.2015.09.013

9.     Ajitkumar A, Yarrarapu SNS, Ramphul K. Chediak-Higashi syndrome. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.

10.  National Institutes for Health. Severe combined immunodeficiency (SCID). National Institute for Allergy and Infectious Diseases, https://www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid, Accessed Jan 19, 2024.

11.  Yazdani R, Fekrvand S, Shahkarami S et al. The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin Immunol. 2019 Jan;198:19-30. doi:10.1016/j.clim.2018.11.007

12.  Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol. 2013 Sep;132(3):515-525. doi:10.1016/j.jaci.2013.07.020

13.  El Hussein S, Medeiros LJ, Khoury JD. Aggressive NK cell leukemia: Current state of the art. Cancers (Basel). 2020 Oct 9;12(10):2900. doi:10.3390/cancers12102900