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Shining light on the significance of NK cell CD56 brightness

Cellular & Molecular Immunology volume 15, pages 1071–1073 (2018)Cite this article

CD56 is a fundamental marker in the determination of human natural killer (NK) cell subsets. The degree of CD56 expression is ubiquitously used to define human NK cell maturation, functional, and tissue-specific subsets, yet a unifying implication for the degree of CD56 expression in NK cells remains elusive. Peripheral blood (PB)-NK cells are dichotomized into CD56bright, which highly express CD56, and CD56dim, which have lower CD56 expression. Classically, CD56bright NK cells are considered to be a less mature, immunoregulatory subset with a greater propensity for cytokine production, whereas CD56dim are more mature with greater cytotoxic abilities. While PB-NK cells are primarily CD56dim with only a minor CD56bright population, NK cells in secondary lymphoid and other tissues are predominantly CD56bright.1 It has been shown that the interaction of CD56 with human fibroblast cells can promote the differentiation of CD56bright to CD56dim NK cells.2 However, considering the importance and the extent of use of this marker in NK cell biology, relatively little is known about how downregulation of CD56 contributes to NK cell maturation, what role the degree of CD56 expression plays in contexts separate from NK cell maturation, and whether CD56 has an active functional role in mature NK cells. Moreover, while CD56bright NK cells were classically considered immunoregulatory, evidence is emerging to suggest that CD56bright NK cells also comprise the most highly cytotoxic of NK cell subsets, producing contradictory implications for CD56 brightness. Given this, we ask: is there a unifying implication for the degree of CD56 brightness across NK cells? Herein, we explore the wide-ranging functions of CD56bright NK cells in order to determine a unified meaning for the degree of CD56 brightness and shed new light on the implications of CD56 brightness in NK cell biology.

In different settings, CD56bright NK cells can have vastly divergent functions. In their most classic definition, they are immunoregulatory and play important regulatory roles in numerous contexts. A seminal study by Hanna et al. revealed that decidual NK cells (dNK), which are superbright for CD56 expression, play a critical role in tissue remodeling during pregnancy.3 They demonstrated that noncytotoxic CD56superbright dNK cells promote trophoblast invasion through secretion of IL-8 and IP-10, and support angiogenesis through secretion of VEGF and PLGF. In contrast to the classic anti-tumor and anti-viral functions induced by NK cell activation, receptor-mediated activation of dNK cells enhanced the secretion of these tissue-modeling factors, revealing a distinct activation-induced functional profile. Due to these tissue-remodeling capabilities, dNK cells in fact improved tumor growth and vascularization of trophoblast choriocarcinomas.3 Indeed, regulatory mechanisms have important implications that also extend to NK cells in the context of cancer. In contrast to anti-tumor splenic NK cells, our group has demonstrated that tumor-associated murine NK cells have a less mature phenotype and exhibit reduced expression of activation receptors, perforin, and granzyme B.4 Similarly, in humans, tumor-associated NK cells are enriched in the less mature CD56bright subset and in many ways resemble dNK cells. The presence of CD56bright cells within a tumor correlates with poor prognosis and reduced time to disease recurrence following therapy.5,6 In addition, Crome et al. demonstrated that CD56+ TILs have impaired anti-tumor cytotoxicity and negatively regulate T cell expansion, TNFα, and IFN-γ production.5 The regulation of T cells by CD56bright NK cells has also been reported to play an important role in the attenuation of autoimmune disease. For example, Bielekova et al. demonstrated that daclizumab therapy, a mAb against the IL-2Rα chain, exerted its therapeutic effects in patients with multiple sclerosis by inducing the expansion of CD56bright NK cells.7 The expansion of CD56bright cells is correlated with reduced brain inflammation and reduced T cell populations. While regulatory CD56bright NK cells are considered to have poor cytotoxicity against tumor targets, these CD56bright NK cells inhibited the survival of activated autologous T cells through direct cytotoxicity.7 Thus, in these studies, CD56bright cells have a strong propensity for regulatory function in response to activation signals.

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Acknowledgements

A.A.A. holds a grant from the Juravinski Hospital and Cancer Center Foundation and a Tier 1 Canada Research Chair. S.M.P. holds an Ontario Women’s Health Scholars Award funded by the Ontario Ministry of Health and Long-Term Care.

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  1. Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada

    Sophie M. Poznanski & Ali A. Ashkar

  2. McMaster University, 1280 Main Street West, MDCL 4015, Hamilton, ON, Canada

    Ali A. Ashkar

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A.A.A. and S.M.P. designed and wrote the article and produced the figure.

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Correspondence to Ali A. Ashkar.

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Poznanski, S.M., Ashkar, A.A. Shining light on the significance of NK cell CD56 brightness. Cell Mol Immunol 15, 1071–1073 (2018). https://doi.org/10.1038/s41423-018-0163-3

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