Natural killer cell

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 10.06.2021

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Synonym(s)

killer cells; Large granular lymphocytes; LGL; Natural killer cell, NK cell; Natural killer cells; NK cells

General information
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NK cells are activated by several activating receptors and co-receptors (including KIR molecules, NKG2 with CD94 and natural cytotoxic receptors), which are able to recognize ligands on virus-infected or tumor cells. The activity of NK cells increases after contact with the cytokines IFN-alpha, INF-beta, IL-12, IL-15, IL-2.

NK cells can be identified in the laboratory using the markers CD16 and CD56. In the blood they are defined as CD3-/CD56+. Overlaps with other surface markers are possible. Monocytes, macrophages, neutrophil granulocytes and eosinophil granulocytes are also capable of this type of target cell recognition.

In the blood, NK cells can be recognized by large azurophilic granules, which also led to the designation "Large Granular Lymphocytes" (LGL) before their actual function became known. Cytotoxic proteins such as perforin or granzyme B are stored in these granules. Perforin is very similar to the C9 complement protein and causes channel-like pores in the membrane of cells or bacteria. Granzyme B enters the cytosol of the cells through these pores and induces apoptosis.

Normally, tumor cells or infected cells are already recognized and eliminated by cytotoxic T lymphocytes due to foreign antigens that they present on their surface in complex with the MHC-I molecules. However, some viruses are able to suppress the presentation of MHC-I molecules on the surface of their host cells. In this way they escape destruction by T-lymphocytes. The reduced expression of the MHC molecules on tumour cells and on virally infected cells is now noticed by the NK cells. They are activated by this and lyse the target cells (Missing-self hypothesis; Ljunggren HG et al. 1990).

This is an essential protection in the early phase of viral infections and seems to activate the antigen-presenting cells (APZ) via the triggered alarm signal in such a way that they can induce specific immune responses.

Note(s)
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For a long time it was unclear how NK cells without inhibitory receptors generate self-tolerance. To protect healthy cells from autoaggression by NK cells, these cells are equipped with strong inhibitory receptors(KIRs = Killer Inhibitory Receptors, and NKG2A) that recognize HLA - class -I - molecules on target cells. In vivo, the anti-tumour function mediated by NK cells can be suppressed by inhibitory soluble factors/cytokines or by the involvement of so-called immune checkpoint molecules (e.g. PD1-PDL1) (Beldi-Ferchiou A et al. 2017). The investigation of these immune checkpoints now offers new important possibilities for tumor therapy (Del Zotto G et al. 2017).

Literature
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  1. Becker PS et al (2016) Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunol Immunother 65:477-484.
  2. Beldi-Ferchiou A et al. (2017) Control of NK Cell Activation by Immune Checkpoint Molecules. Int J Mol Sci 18. pii: E2129. 10.3390/ijms18102129.
  3. Cheng M et al (2013) NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 10:230-252.
  4. Del Zotto G et al (2017) Markers and function of human NK cells in normal and pathological conditions. Cytometry B Clin Cytom 92:100-114.
  5. Ljunggren HG et al (1990) In search of the 'missing self': MHC molecules and NK cell recognition. In: Immunology Today 11: 237-244
  6. Zhang C et al (2017) NK cell subsets in autoimmune diseases. J autoimmune 83:22-30.

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Last updated on: 10.06.2021