Human Circulating and Tissue-Resident CD56(bright) Natural Killer Cell Populations

Abstract

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.

Keywords: CD56bright NK cell populations; NK cell development; liver; lymphoid tissues; tissue resident; uterus.

Figure 1

Distribution of NK cell populations in blood and tissues. The distribution of CD56^dim, non-resident CD56^bright, and tissue-resident CD56^bright NK cells is depicted as percentage of (A) total lymphocytes and (B) total NK cells within blood (13), lymph node (13, 18, 25), spleen (13, 18, 25), bone marrow (13, 18, 25), tonsil (18, 44), liver (15, 45, 46), endometrium (16, 20), and decidua (20, 47). Tissue-resident CD56^bright NK cells were defined as CD69⁺CXCR6⁺ (lymph node, spleen, and bone marrow), NKp44⁺CD103⁺ (tonsil), CD69⁺CXCR6⁺ (liver), and CD49a⁺ (endometrium and decidua). For phenotypical details, see Figure 2 and Table 1.

Figure 2

Phenotype of circulating and tissue-resident CD56^bright NK cells. The cell surface markers on NK cells that are discriminative between circulating and tissue-resident NK cells in lymphoid tissue, liver, and uterus are shown (see references in text and Table 1). Circulating CD56^bright NK cells typically express the lymphoid tissue homing makers CD62L (L-selectin) and CCR7. In addition, CD117 (c-kit) and CD127 (IL-7Rα) are expressed by a fraction of circulating CD56^bright NK cells. Lymphoid tissue-resident NK cells express CD69 and CXCR6. Tonsil-resident NK cells (defined as NKp44⁺CD103⁺) express in addition ITGβ7, CD49a, and partly CD9. The majority of CD69⁺CXCR6⁺ liver-resident NK cells express CCR5. In contrast to circulating CD56^bright NK cells, only a fraction of lymphoid tissue-, tonsil-, and liver-resident NK cells express DNAM1. A subset of CD49a⁺ uterus-resident NK cells (endometrium and decidua) expresses CD69, ITGβ7, CD103, and NKp44. The reported DNAM1 expression in the uterus is contradicting in the literature and therefore indicated with −*. % indicates that only a fraction of the NK cell population is positive for the marker.