Human Circulating and Tissue-Resident CD56bright Natural Killer Cell Populations

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.

The Broad Spectrum of Human Natural Killer Cell Diversity

“…These various populations of human trNK cells described to date share a number of common features with each other and are overall quite distinct from PB CD56 bright cNK cells (Melsen et al, 2016). First of all, trNK cells lack expression of CCR7 and CD62L, which are characteristically expressed by PB CD56 bright cNK cells.…”

“…Given their presence and relatively high frequencies in so many tissues, including the numerous SLTs throughout the body, it is intriguing that, contrary to original belief, CD56 bright cNK cells are more abundant than CD56 dim cNK cells. Nonetheless, CD56 bright cNK cells may not be the most abundant NK cell subset overall, as numerous recent reports reveal marked heterogeneity within tissues due to the presence of specialized trNK cells that share some immunophenotypic and functional features with CD56 bright cNK cells but that are otherwise distinct (Melsen et al, 2016). …”

“…For many years it has been appreciated that CD56 bright CD16 − NK cells represent the predominant NK cell population in both SLTs and in the uterus where their respective functions likely include promoting T helper-1 (Th1) cell-associated responses and in facilitating decidual changes associated with pregnancy such as vascular remodeling (Gaynor and Colucci, 2017; Melsen et al, 2016). In human LNs and tonsils NK cells are relatively rare and represent up to only 1–2% of total lymphocytes.…”

“…Recent studies have expanded on this definition by characterizing NK cells within additional human tissues each possessing distinct phenotypic profiles as indicated. The CD56 bright cNK cell in the blood shares some common features with several of these non-conventional trNK cell populations, but it is becoming clear that trNK are actually quite distinct functionally as well as immunophenotypically (Björkström et al, 2016; Freud et al, 2014; Melsen et al, 2016). Likewise, we are now appreciating the high amounts of diversity within the CD56 dim cNK cell population, as by the generation of adaptive NK cells in response to environmental stimuli such as virally infected cells or cancer (Björkström et al, 2016; Schlums et al, 2015).…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Although some of these may include organ‐infiltrating NK cells, bona fide tissue‐resident CD56 bright NK cells have also recently been described (reviewed in110). These cells are retained in the tissues through their expression of CD69, chemokine receptors such as CXCR6 and CCR5, as well as adhesion molecules such as CD49a.…”