Human Circulating and Tissue-Resident CD56bright Natural Killer Cell Populations

Two human natural killer (NK) cell subsets are usually distinguished, displaying the CD56(dim)CD16(+) and the CD56(bright)CD16(-/+) phenotype. This distinction is based on NK cells present in blood, where the CD56(dim) NK cells predominate. However, CD56(bright) NK cells outnumber CD56(dim) NK cells in the human body due to the fact that they are predominant in peripheral and lymphoid tissues. Interestingly, within the total CD56(bright) NK cell compartment, a major phenotypical and functional diversity is observed, as demonstrated by the discovery of tissue-resident CD56(bright) NK cells in the uterus, liver, and lymphoid tissues. Uterus-resident CD56(bright) NK cells express CD49a while the liver- and lymphoid tissue-resident CD56(bright) NK cells are characterized by co-expression of CD69 and CXCR6. Tissue-resident CD56(bright) 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 CD56(bright) NK cells exert tissue-specific functions. In this review, we examine the CD56(bright) NK cell diversity by discussing the distribution, phenotype, and function of circulating and tissue-resident CD56(bright) NK cells. In addition, we address the ongoing debate concerning the developmental relationship between circulating CD56(bright) and CD56(dim) NK cells and speculate on the position of tissue-resident CD56(bright) NK cells. We conclude that distinguishing tissue-resident CD56(bright) NK cells from circulating CD56(bright) NK cells is a prerequisite for the better understanding of the specific role of CD56(bright) NK cells in the complex process of human immune regulation.