Abstract
Two human natural killer (NK) cell subsets are usually distinguished, displaying the CD56dimCD16+ and the CD56brightCD16−/+ phenotype. This distinction is based on NK cells present in blood, where the CD56dim NK cells predominate. However, CD56bright NK cells outnumber CD56dim NK cells in the human body due to the fact that they are predominant in peripheral and lymphoid tissues. Interestingly, within the total CD56bright NK cell compartment, a major phenotypical and functional diversity is observed, as demonstrated by the discovery of tissue-resident CD56bright NK cells in the uterus, liver, and lymphoid tissues. Uterus-resident CD56bright NK cells express CD49a while the liver- and lymphoid tissue-resident CD56bright NK cells are characterized by co-expression of CD69 and CXCR6. Tissue-resident CD56bright NK cells have a low natural cytotoxicity and produce little interferon-γ upon monokine stimulation. Their distribution and specific phenotype suggest that the tissue-resident CD56bright NK cells exert tissue-specific functions. In this review, we examine the CD56bright NK cell diversity by discussing the distribution, phenotype, and function of circulating and tissue-resident CD56bright NK cells. In addition, we address the ongoing debate concerning the developmental relationship between circulating CD56bright and CD56dim NK cells and speculate on the position of tissue-resident CD56bright NK cells. We conclude that distinguishing tissue-resident CD56bright NK cells from circulating CD56bright NK cells is a prerequisite for the better understanding of the specific role of CD56bright NK cells in the complex process of human immune regulation.
Highlights
Since the discovery of natural killer (NK) cells in 1975 [1, 2], major advances were made in deciphering the role of NK cells in health and disease
The recent identification of tissue-resident CD56bright NK cells in the lymphoid tissues, liver, and uterus led us to reappraise the characteristics of CD56bright NK cell populations in the circulation and tissues
The function of tissue-resident CD56bright NK cells in liver and lymphoid tissues has not been elucidated, it is very likely that these cells, such as uterine NK cells, exert tissue-specific functions
Summary
Since the discovery of natural killer (NK) cells in 1975 [1, 2], major advances were made in deciphering the role of NK cells in health and disease. It is currently accepted that NK cells are not just “killers” that lyse infected or transformed cells but can play an important role in modulation of immune responses due to the secretion of immunoregulatory cytokines (e.g., IFN-γ and TNF-α) and chemokines (e.g., CCL3 and CCL4). Based on this cytokine secretion profile, NK cells are classified into group 1 of the large family of innate lymphoid cells (ILCs). Based on circulating NK cells, CD56bright and CD56dim NK cells have usually been described as two functionally distinct subsets, cytokine producing and cytolytic, respectively.
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