Trends in Immunology
Volume 22, Issue 11, 1 November 2001, Pages 633-640
Journal home page for Trends in Immunology

Review
The biology of human natural killer-cell subsets

https://doi.org/10.1016/S1471-4906(01)02060-9Get rights and content

Abstract

Human natural killer (NK) cells comprise ≈15% of all circulating lymphocytes. Owing to their early production of cytokines and chemokines, and ability to lyse target cells without prior sensitization, NK cells are crucial components of the innate immune system. Human NK cells can be divided into two subsets based on their cell-surface density of CD56 – CD56bright and CD56dim – each with distinct phenotypic properties. Now, there is ample evidence to suggest that these NK-cell subsets have unique functional attributes and, therefore, distinct roles in the human immune response. The CD56dim NK-cell subset is more naturally cytotoxic and expresses higher levels of Ig-like NK receptors and FCγ receptor III (CD16) than the CD56bright NK-cell subset. By contrast, the CD56bright subset has the capacity to produce abundant cytokines following activation of monocytes, but has low natural cytotoxicity and is CD16dim or CD16. In addition, we will discuss other cell-surface receptors expressed differentially by human NK-cell subsets and the distinct functional properties of these subsets.

Section snippets

Phenotypic properties of human NK-cell subsets

The CD56 antigen is an isoform of the human neural-cell adhesion molecule with unknown function on human NK cells 3, although early studies suggested that this molecule might mediate interactions between NK cells and target cells 4, 5. Thus, there is no known direct functional significance of high- or low-level expression of CD56. However, there are a number of other cell-surface markers that confer unique phenotypic and functional properties to CD56bright and CD56dim NK-cell subsets (Table 1).

Cytotoxicity

Activation of NK-cell cytotoxicity is thought to be mediated by a balance of inhibitory and activatory NKRs, as well as various adhesion and costimulatory molecules 24, 39. Early studies of resting CD56dim NK cells revealed that these cells are naturally more cytotoxic than CD56bright NK cells 40, although after activation with IL-2 or IL-12 in vitro, or following low dose therapy with IL-2, CD56bright and CD56dim cells have similar levels of cytotoxicity 9, 10, 41. Consistent with differences

NK-cell subset development

It has been known for decades that NK cells develop within the microenvironment of the bone marrow (BM), and numerous studies have identified definitively IL-15 as the crucial factor for the development of human and murine NK cells 48, 49, 50, 51. IL-15 was first identified as a product of normal BM stroma that could induce differentiation of human hematopoietic progenitor cells (HPCs) into NK cells in the absence of other cytokines in vitro 48. When added to BM HPCs, flt3 ligand (FL) or KL

NK-cell subsets in physiological and disease states

In contrast to being a minor population of NK cells in human peripheral blood, CD56bright NK cells appear to be the major NK-cell subset in the uterus of a pregnant woman (reviewed in Ref. 56). The exact function of these decidual NK cells is unknown, and these cells differ slightly from peripheral-blood CD56bright NK cells in phenotype and function. They do, however, express cytokine receptors constitutively, produce immunoregulatory cytokines and lyse target cells, similar to circulating CD56

Concluding remarks

Recent evidence has suggested that human NK-cell subsets are distinct lymphocytes with unique roles in the innate immune response (Fig. 4). In addition to distinct expression of adhesion molecules and cytokine receptors, the CD56bright NK cell has the capacity to produce high levels of immunoregulatory cytokines, but has low-level expression of KIRs and is poorly cytotoxic (Fig. 4a). By contrast, the CD56dim NK cell appears to produce low levels of cytokines but has high-level expression of

Acknowledgements

Our work was supported by grants CA-68458 and P30CA-016058 from the National Institutes of Health. M.A. Cooper and T.A.F. are recipients of Medical Scientist Program Fellowships from the Ohio State University College of Medicine and Public Health.

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