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Emerging insights into natural killer cells in human peripheral tissues

Key Points

  • Natural killer (NK) cells are present in most human tissues. A high frequency of NK cells can be found in peripheral blood, the lungs, the uterus and the liver, whereas NK cells are scarce in lymph nodes and tonsils, as well as some other peripheral organs.

  • NK cells in humans are highly diverse. This diversity is generated by developmentally distinct NK cell subsets, killer cell immunoglobulin-like receptor (KIR) expression, NK cell differentiation, clonal-like expansion in response to pathogens and tissue distribution.

  • The current paradigm holds that NK cells develop in the bone marrow and secondary lymphoid tissues. However, emerging evidence also supports a 'peripheral view' of NK cell development with precursors capable of progressing into mature NK cells present in many peripheral tissues.

  • Tissue-resident NK cells are characterized by surface expression of CD69, CD103 and CD49a; however, a detailed characterization of tissue-resident NK cells is still lacking for many human tissues.

  • Tissue-resident NK cells exhibiting a CD56bright phenotype dominate certain peripheral tissues, such as the gut, tonsils, lymph nodes and skin, whereas other sites, such as the lungs and the liver, contain higher frequencies of CD56dim cells. The uterus contains a unique subset of NK cells sharing features of both CD56bright and CD56dim cells.

  • It is clear that many peripheral tissues contain tissue-resident NK cells. However, we currently lack knowledge of the role of these cells in numerous human diseases.

Abstract

Natural killer (NK) cells have long been considered to be a homogenous population of innate lymphocytes with limited phenotypic and functional diversity. However, recent findings have revealed that these cells comprise a large number of distinct populations with diverse characteristics. Some of these characteristics may relate to their developmental origin, and others represent differences in differentiation that are influenced by factors such as tissue localization and imprints by viral infections. In this Review, we provide a comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues.

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Figure 1: Diversity of human NK cell populations.
Figure 2: Characteristics of human NK cells in circulation and peripheral tissues.
Figure 3: Proposed model for development of NK cells in human peripheral tissues.

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Acknowledgements

The authors thank present and past members of their groups for their contributions towards the understanding of human NK cells in health and disease. Their work has been supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Swedish Society for Medical Research, the Cancer Research Foundations of Radiumhemmet, the Swedish Society of Medicine, the Novo Nordisk Foundation, Åke Wiberg's Foundation, Åke Olsson's Foundation, Bengt Ihre's Foundation, Magnus Bergwalls Foundation, the Stockholm County Council, the Tobias Foundation, the Swedish Foundation for Strategic Research and the Karolinska Institutet. The authors apologize to colleagues whose work has not been cited owing to space constraints.

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Glossary

Killer cell immunoglobulin-like receptors

(KIRs). A polygenic and highly polymorphic family of receptor molecules recognizing primarily HLA class I ligands in humans; natural killer (NK) cells are the major KIR-expressing cells. A salient feature of KIRs is their stochastic distribution of cell-surface expression across the NK cell compartment, resulting in highly diverse NK cell KIR repertoires unique for each individual and population.

NK cell education

A functional maturation process of natural killer (NK) cells involving initial interaction between inhibitory NK cell receptors and self-MHC class I molecules. NK cells that express inhibitory receptors only to non-self MHC class I molecules or lack expression of inhibitory receptors are maintained through this mechanism in a hyporesponsive (tolerant) mode, preventing auto-aggression.

Cytomegalovirus

(CMV). A herpesvirus infecting a large proportion of the human population. Natural killer (NK) cells are crucial for the control of CMV; however, the virus also has multiple immune evasion mechanisms that target NK cell functions and establish latency.

Parabiosis

Experimental technique in which two animals are surgically joined to create a shared circulatory system.

Decidua

The endometrium that undergoes changes to support placentation during pregnancy. The decidua, which is in direct contact with the placenta, contains spiral arteries that are remodelled during pregnancy to become less convoluted and develop an enlarged diameter to increase maternal blood flow to the placenta.

Liver sinusoids

A type of sinusoidal blood vessels that contain slow-flowing blood from the oxygen-rich hepatic artery and the nutrient-rich portal venous system.

Kupffer cells

A specialized macrophage population that lines the walls of the liver sinusoids. These antigen-presenting cells remove microbial products and endotoxins from the portal venous blood and regulate intrahepatic immune responses.

Tissue residency

A characteristic of immune cells that occupy non-lymphoid tissues without apparent recirculation via the lymphatic system or blood.

Hepatic stellate cells

A specialized cell type that is present in the perisinusoidal space of the liver, representing the major vitamin A-storing cells of the body. When aberrantly activated, these cells secrete collagen and contribute to liver fibrosis development.

Endometrium

An outer mucosal surface of the uterus consisting of a single layer of epithelium and a lamina propria, which contains tubular glands and spiral arteries. The functional layer of the endometrium is built up during each menstrual cycle.

Alemtuzumab

A medication that depletes CD52-expressing circulating immune cells, including natural killer cells, as a therapy for patients with lymphoma.

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Björkström, N., Ljunggren, HG. & Michaëlsson, J. Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol 16, 310–320 (2016). https://doi.org/10.1038/nri.2016.34

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