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  • Review Article
  • Published:

NK cell development, homeostasis and function: parallels with CD8+ T cells

Key Points

  • Natural killer (NK) cell development in the bone marrow consists of an education process that involves inhibitory receptor engagement with MHC class I molecules, in a similar manner to thymic selection dictated by T cell receptor (TCR)–MHC interactions.

  • NK cell lineage specification depends on intrinsic programming by transcription factors such as ID2 and E4BP4.

  • After exiting the bone marrow, NK cells undergo a progressive phenotypic and functional maturation. Peripheral NK cell homeostasis and survival require IL-15.

  • In a lymphopenic environment, NK cells rapidly undergo homeostatic proliferation in order to fill the NK cell niche. This expansion results in the generation of long-lived NK cells capable of robust effector responses.

  • During certain viral infections in mice and humans, NK cells are activated, undergo prolific clonal expansion and become long-lived memory cells capable of increased responsiveness; this response closely resembles the CD8+ T cell response against pathogens.

Abstract

Natural killer (NK) cells survey host tissues for signs of infection, transformation or stress and, true to their name, kill target cells that have become useless or are detrimental to the host. For decades, NK cells have been classified as a component of the innate immune system. However, accumulating evidence in mice and humans suggests that, like the B and T cells of the adaptive immune system, NK cells are educated during development, possess antigen-specific receptors, undergo clonal expansion during infection and generate long-lived memory cells. In this Review, we highlight the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8+ T cell.

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Figure 1: Education of developing NK cells and thymocytes.
Figure 2: Factors that influence the development, homeostasis and survival of NK cells and T cells.
Figure 3: Antigen-specific and -nonspecific responses of NK cells and CD8+ T cells during infection.
Figure 4: Comparing the reactivity of NK cells and CD8+ T cells during differentiation.

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Acknowledgements

The authors thank S. Jameson, J. van Heijst and G. Gasteiger for helpful discussions and critical reading of the manuscript. J.C.S. is supported by the Searle Scholars Program and US National Institutes of Health (NIH) grant AI085034. L.L.L. is an American Cancer Society Professor and is supported by NIH grants AI068129, AI066897 and CA095137.

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Glossary

Perforin and granzymes

The cytolytic molecules that are secreted by NK cells and cytotoxic CD8+ T cells. Perforin subunits assemble into a pore-forming structure in the membrane of the target cell, and this allows granzymes (a family of proteolytic enzymes) to activate caspases and induce apoptosis in the target cell.

Clonal expansion

The process whereby individual B and T cells that express unique antigen-specific receptors encounter their cognate ligands and rapidly proliferate to give rise to a large number of progeny that express the same antigen-specific receptor (that is, clones).

NK1.1

(Also known as KLRB1C and NKRP1C). This activating receptor associates with the adaptor molecule FcɛRIγ and is expressed on all NK and NKT cells in C57BL/6 mice. Although crosslinking of the receptor using an NK1.1-specific mAb (clone PK136) induces NK cell-mediated cytotoxicity and effector cytokine secretion, the in vivo function of NK1.1 and nature of its ligand(s) remain unknown.

NKG2D

(Natural killer group 2, member D). An activating receptor constitutively expressed on NK cells and activated CD8+ T cells that recognizes a family of induced host ligands on the surface of stressed cells. DNA instability and damage arising from radiation, chemicals, infection or transformation can lead to cellular stress and the upregulation of NKG2D ligands (namely, the retinoic acid early-inducible protein 1 (RAE1) family, histocompatibility antigen 60 (H60) and murine UL16-binding protein-like transcript 1 (MULT1) in mice, and the MHC class I polypeptide-related sequence (MIC) and UL16-binding protein (ULBP) families in humans).

LY49 receptors

A family of NK cell receptors in mice that contains inhibitory members that bind to MHC class I molecules and inhibit NK cell responses and activating members that predominantly associate with the adaptor molecule DAP12 to initiate effector functions following encounter with target cells that express cognate ligands. The ligands for the majority of activating LY49 receptors are currently unknown; however, some are likely to be virally encoded components.

Positive selection

A process during T cell development whereby double-positive (CD4+CD8+) thymocytes are selected to survive and mature into single-positive (CD4+ or CD8+) T cells based on an appropriate degree (low to intermediate) of stimulation through the T cell receptor.

'Missing-self'

A hypothesis proposed by Klas Karre suggesting that NK cells preferentially recognize and kill host cells that have lost expression of self MHC class I molecules — in other words, cells that are 'missing self'. Uninhibited by immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors for MHC class I molecules, NK cells can target virally infected or transformed cells that downregulate MHC class I molecules to evade detection by CD8+ T cells.

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Sun, J., Lanier, L. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nat Rev Immunol 11, 645–657 (2011). https://doi.org/10.1038/nri3044

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