Key Points
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Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals in target organs of disease. However, the role of NK cells in regulating inflammatory responses is far from completely understood in different organs. It is often complex and sometimes paradoxical.
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The phenotypes and functions of NK cells in the liver, mucosal tissues, uterus, pancreas, joints and brain are influenced by the unique cellular interactions and the local microenvironment within each organ.
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Hepatic NK cells exhibit an activated phenotype with high levels of cytotoxic effector molecules. These cells have been implicated in promoting liver injury and inhibiting liver fibrosis and regeneration. The liver is also enriched in NK cells with memory-like adaptive immune features.
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NK cells are detected in healthy lymphoid tissues of the lung, skin and gut, and are recruited to these tissues during infection or inflammation. In the gastrointestinal tract, classical NK cells and a variety of innate lymphoid cells, such as the family of lymphoid tissue-inducer (LTi) cells, are likely to have crucial roles in controlling inflammatory responses.
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NK cells represent the major lymphocyte subset in the pregnant uterus, with a unique phenotype resembling an early developmental state. Emerging evidence indicates that these cells play a crucial part in mediating the uterine vascular adaptations to pregnancy and promoting the maintenance of healthy pregnancy.
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In non-obese diabetic (NOD) mice, NK cells are recruited early to the pancreas, become locally activated and then adopt a hyporesponsive phenotype. Although NK cells have a pathogenic role in the natural progression of diabetes in NOD mice, they contribute to diabetes protection induced by complete Freund's adjuvant and to islet allograft tolerance induced by co-stimulatory blockade.
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NK cells in the inflamed joint uniquely express receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which promote osteoclast differentiation. Although NK cells have a pathogenic role in collagen-induced arthritis in mice, they are also crucial for protection against antibody-induced arthritis mediated by CpG oligonucleotides.
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Studies in a mouse model of multiple sclerosis have shown that NK cells arrive in the central nervous system (CNS) before pathogenic T cells and have a protective role in the development of CNS inflammation, probably by killing CNS-resident microglia that prime effector T cells.
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During evolution, different organs might have evolved distinct ways to recruit and influence the effector functions of NK cells. Once we understand these mechanisms, the next challenge will be to exploit this information for harnessing NK cells to develop prophylactic and therapeutic measures against infectious agents, tumours and inflammatory diseases.
Abstract
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.
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Change history
18 November 2011
In the original version of this article, in the section under the subheading “CNS-specific NK cells in disease” on page 668, the humanized antibody daclizumab was incorrectly described as being specific for the IL-2 receptor β-chain (CD122). The corrected sentence now reads: “These findings might be relevant to the mode of action of daclizumab, a humanized antibody specific for the IL-2 receptor α-chain (CD25)”. The authors apologize for this error.
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Acknowledgements
We thank present and past members of our laboratories for their contributions towards the understanding of NK cells in health and disease. We also thank Z. Tian, N. Björkström and Z. Tu for fruitful discussions and advice, and R. Liu, Y. Gan and S. Shi for assistance in preparing the manuscript. The authors' clinical and laboratory programmes are supported by the National Science Foundation of China (31170864 to F.-D.S.), the US Muscular Dystrophy Association (159281 to F.-D.S.), the Arizona Biomedical Research Commission (09-085 to F.-D.S.), the US National Institutes of Health (RO1AI083294 to F.-D.S.; RO1AR53295 to A.L.C.; and RO1AI070305, R21AI072417, RO1DK081536 and RO1HL089667 to L.V.K.), the Swedish Research Council (H.-G.L.), the Swedish Cancer Society (H.-G.L.), the Tobias Foundation (H.-G.L.), the Karolinska Institutet (H.-G.L.), and the Stockholm County Council (H.-G.L.). We apologize to those colleagues whose work has not been cited owing to space constraints.
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Glossary
- Natural killer cells
-
(NK cells). Cytotoxic lymphocytes of the innate immune system. These cells have an important role in host defence against many intracellular pathogens and some tumours, regulate the development of adaptive immunity, and control the homeostasis of other immune cells. Human NK cells express the surface marker CD56, and mouse NK cells express the surface markers DX5 (CD49b) and, in some mouse strains (for example, C57BL/6), NK1.1 (CD161).
- Type 1 diabetes
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A form of diabetes caused by autoimmune destruction of insulin-producing pancreatic β-cells. Autoimmune destruction is predominantly mediated by CD8+ T cells, but natural killer cells may affect disease outcome.
- Rheumatoid arthritis
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A systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The disease process produces an inflammatory response of the synovium (synovitis), secondary to hyperplasia of synovial cells, excess synovial fluid and the development of pannus in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis of the joints.
- Kupffer cell
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Also known as Browicz–Kupffer cells, Kupffer cells are specialized macrophages that line the walls of the liver sinusoids.
- Natural killer T cells
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(NKT cells). A subset of T cells that are specific for lipid or glycolipid antigens bound to the MHC class I-related protein CD1d. Most NKT cells, which are referred to as type I or invariant NKT (iNKT) cells, express an invariant T cell receptor-α chain (Vα14–Jα18 in mice or Vα24–Jα18 in humans) together with various natural killer cell surface markers, such as NK1.1. NKT cells have a regulatory role during an immune response, bridging the innate and adaptive immune systems. iNKT cells can be most easily identified with multimeric CD1d molecules loaded with iNKT cell agonists, such as α-galactosylceramide.
- Trophoblast layer
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A layer formed by trophoblast cells that arise from the trophectoderm that surrounds the blastocyst. The trophoblast layer attaches the embryo to the uterus and forms a part of the placenta.
- Collagen-induced arthritis
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A model for human rheumatoid arthritis that is induced in susceptible strains of mice or rats by immunization with autologous or heterologous type II collagen in adjuvant.
- K/BxN mice
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K/BxN mice express a transgene-encoded T cell receptor that is specific for the ubiquitously expressed enzyme glucose-6-phosphate isomerase, which is presented by the MHC class II molecule H2-Ag7. These mice spontaneously develop joint inflammation with features of human rheumatoid arthritis. Interestingly, transfer of serum from arthritic animals into healthy non-transgenic animals induces arthritis in a highly reproducible and controlled manner.
- Microglia
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Non-neuronal cells of the central nervous system with phagocytic properties. They are haematopoietic cells and are involved in inflammatory and immune responses in the central nervous system.
- Experimental autoimmune encephalomyelitis
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(EAE). An experimental model for human multiple sclerosis that can be induced in susceptible animals by immunization with neuroantigens and adjuvant.
- Multiple sclerosis
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An inflammatory and demyelinating disease of the central nervous system that is primarily diagnosed in young adults. Clinical presentations are heterogeneous depending on the severity and location of central nervous system lesions.
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Shi, FD., Ljunggren, HG., La Cava, A. et al. Organ-specific features of natural killer cells. Nat Rev Immunol 11, 658–671 (2011). https://doi.org/10.1038/nri3065
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DOI: https://doi.org/10.1038/nri3065
