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Review
. 2021 Apr;27(3):212-229.
doi: 10.1177/17534259211001512. Epub 2021 Mar 24.

Human NK cells: From development to effector functions

Arosh Shavinda Perera Molligoda Arachchige  1
Affiliations
Review

Human NK cells: From development to effector functions

Arosh Shavinda Perera Molligoda Arachchige. Innate Immun. 2021 Apr.

Abstract

NK cells are the major lymphocyte subset of the innate immune system that mediates antiviral and anti-tumor responses. It is well established that they develop mechanisms to distinguish self from non-self during the process of NK cell education. Unlike T and B cells, natural killer cells lack clonotypic receptors and are activated after recognizing their target via germline-encoded receptors through natural cytotoxicity, cytokine stimulation, and Ab-dependent cellular cytotoxicity. Subsequently, they utilize cytotoxic granules, death receptor ligands, and cytokines to perform their effector functions. In this review, we provide a general overview of human NK cells, as opposed to murine NK cells, discussing their ontogeny, maturation, receptor diversity, types of responses, and effector functions. Furthermore, we also describe recent advances in human NK cell biology, including tissue-resident NK cell populations, NK cell memory, and novel approaches used to target NK cells in cancer immunotherapy.

Keywords: Natural killer; activation; development; education; functions; receptors.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Appendix Figure 1.
Appendix Figure 1.
Different models explaining NK cell education. (A) Precursor NK cells develop into armed NK cells after recognition of self MHC-I. The inability to recognize self MHC-I results in a loss of their effector potential. (B) Precursor and/or mature NK cells maintain their effector potential as long as they recognize self MHC-I. The inability to do so leads to disarming. (C) NK cell education is a modulated process and not an ‘on and off’ procedure. NK cell effector potential increases with the increased number of inhibitory receptor-self MHC-I contacts.
Appendix Figure 2.
Appendix Figure 2.
Mechanisms of NK cell target recognition and their corresponding activation thresholds. (A) ‘Normal self’: Increased autologous MHC-I recognition by the NK cell leading to a net inhibition. (B) ‘Missing self’: Net activation of NK cell due to the lack of inhibitory signaling from inhibitory receptor-self MHC-I contact. (C) ‘Altered self’: Activating ligands are induced in the target cell due to stress, possibly caused by an underlying infection, and results in a net activation of the NK cell. (D) ‘Non-self’: NK cell activation when the target cell expresses non-self MHC-I, for example during an allogeneic transplant.
Appendix Figure 3.
Appendix Figure 3.
Functions of NK cells. (A) NK cells suppress GvHD by directly killing T cells or by indirectly killing APCs. Moreover, NK cells can also promote the development of GvHD through the secretion of pro-inflammatory cytokines. (B) NK cells destroy metastatic cells. (C) NK cells destroy infected or stressed cells that display up-regulated activating ligands. (D) uNK cells drive the migration of the trophoblast during pregnancy through the secretion of chemokines. They secrete angiogenic growth factors to promote the remodeling of decidual spiral arteries during the early stages of pregnancy.
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