Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Apr;74(4):397-404.
doi: 10.1136/thoraxjnl-2018-212345. Epub 2018 Oct 31.

Natural killer cells in lung transplantation

Daniel R Calabrese  1 , Lewis L Lanier  2   3 , John R Greenland  1   4
Affiliations
Review

Natural killer cells in lung transplantation

Daniel R Calabrese et al. Thorax. 2019 Apr.

Abstract

Natural killer (NK) cells are innate lymphoid cells that have been increasingly recognised as important in lung allograft tolerance and immune defence. These cells evolved to recognise alterations in self through a diverse set of germline-encoded activating and inhibitory receptors and display a broad range of effector functions that play important roles in responding to infections, malignancies and allogeneic tissue. Here, we review NK cells, their diverse receptors and the mechanisms through which NK cells are postulated to mediate important lung transplant clinical outcomes. NK cells can promote tolerance, such as through the depletion of donor antigen-presenting cells. Alternatively, these cells can drive rejection through cytotoxic effects on allograft tissue recognised as 'non-self' or 'stressed', via killer cell immunoglobulin-like receptor (KIR) or NKG2D receptor ligation, respectively. NK cells likely mediate complement-independent antibody-mediated rejection of allografts though CD16A Fc receptor-dependent activation induced by graft-specific antibodies. Finally, NK cells play an important role in response to infections, particularly by mediating cytomegalovirus infection through the CD94/NKG2C receptor. Despite these sometimes-conflicting effects on allograft function, enumeration of NK cells may have an important role in diagnosing allograft dysfunction. While the effects of immunosuppression agents on NK cells may currently be largely unintentional, further understanding of NK cell biology in lung allograft recipients may allow these cells to serve as biomarkers of graft injury and as therapeutic targets.

Keywords: innate immunity; lung transplantation; lymphocyte biology.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
NK cell receptors and ligands. The NK cell activating and inhibitory receptors that are discussed within this review article are depicted with their associated ligands. HA, haemagglutinin; HLA, human leucocyte antigen; IL, interleukin; IgG, immunoglobulin G; KIR, killer cell immunoglobulin-like receptor; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; MICA/B, MHC class I polypeptide-related sequence A and B; NK, natural killer; ULBP, UL16-binding proteins.
Figure 2
Figure 2
NK cells may mediate lung transplant outcomes. Overview of the potential roles that NK cells play in mediating lung allograft tolerance (right portion of figure) and lung allograft injury (left portion of figure). NK cells may promote allograft tolerance through detection of missing-self and direct cytotoxicity of donor APCs. Stressed donor-specific CD4+ T cells may also be eliminated through the NKG2D receptor on NK cells recognising MICA or other stress-induced ligands on activated T lymphocytes. Allograft injury may occur through several mechanisms, chief of which is perforin-dependent cell-mediated cytotoxicity, augmented by the production of proinflammatory cytokines such as IFNγ in response to IL-12 or IL-18. NK cells are also capable of antibody-dependent cell-mediated cytotoxicity by recognising antibody bound to the allograft (donor-specific antibodies (DSAs)) through the CD16A receptor on the NK cells. Finally, NK cells may also recognise and lyse stressed allograft cells (MICA or other NKG2D ligands on endovascular endothelial surface) through the NKG2D receptor on NK cells. APC, antigen-presenting cell; IFNγ, gamma interferon; IL, interleukin; KIR, killer cell immunoglobulin-like receptor; MHC, major histocompatibility complex; MICA/B, MHC class I chain-related sequence A and B; NKC, natural killer cell.
Figure 3
Figure 3
Possible mechanism for KIR licencing and destruction of donor antigen-presenting cells (APCs). (A) During NK cell maturation, inhibitory receptor KIR3DL1 is licenced by HLA antigens with the Bw4 epitope. (B) After transplantation, a KIR3DL1-Bw4 licenced recipient NK cell contacts a donor APC bearing Bw6 epitope. The absence of a KIR inhibitory signal triggers a host-versus-graft destruction of the recipient APC in conjunction with an activating receptor-ligand interaction such as NKp30 on NK cells and B7-H6 on APC. HLA, human leucocyte antigen; KIR, killer cell immunoglobulin-like receptors; NKC, natural killer cell.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Benichou G, Yamada Y, Aoyama A, et al. Natural killer cells in rejection and tolerance of solid organ allografts. Curr Opin Organ Transplant 2011;16:47–53. - PMC - PubMed
    1. Fildes JE, Yonan N, Leonard CT. Natural killer cells and lung transplantation, roles in rejection, infection, and tolerance. Transpl Immunol 2008;19:1–11. - PubMed
    1. Herberman RB, Nunn ME, Holden HT, et al. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 1975;16:230–9. - PubMed
    1. Kiessling R, Klein E, Wigzell H. Natural killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 1975;5:112–7. - PubMed
    1. Herberman RB, Callewaert DM. Mechanisms of cytotoxicity by NK cells. 669 Orlando: Academic Press, 1985.

Publication types

MeSH terms

Substances