Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

Abstract

Knowledge of human NK cells is based primarily on conventional CD56bright and CD56dim NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30–60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69+CXCR6+ lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69+CXCR6+ NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69+CXCR6+ NK cells produce IFN-γ at levels comparable to CD56dim NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69+CXCR6+ lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69+CXCR6+ NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.

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

“…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. For example, more than 75% of the NK cells in lymph nodes express CD56 at high levels,52, 105 the majority of which express CD69 and CXCR6, and have been shown to be lymphoid tissue‐resident 105. Similar enrichment of both tissue‐resident and circulating CD56 bright NK cells has been found in the spleen, bone marrow and tonsils.…”

“…Furthermore, immature DCs are killed by CD56 bright NK cells in lymph nodes in a TRAIL‐dependent manner,103, 104 and IL‐2‐activated peripheral blood CD56 bright NK cells can become efficient killers 50, 51, 52. Similarly, CD69 + CXCR6 + tissue‐resident CD56 bright NK cells in lymphoid tissues have recently been shown to constitutively express perforin, but require pre‐activation to express GrB and become cytotoxic,105 much like MAIT cells.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Growing evidence indicates that specialized trNK cell populations are present in these tissues and are distinct from their cNK cell counterparts that predominate in PB. For example, trNK cells in human LNs and tonsils have bimodal expression of DNAM-1, have high expression of CD54 (ICAM-1), and have slightly lower expression of CD56 compared to CD56 bright cNK cells in PB (Lugthart et al, 2016; Lunemann et al, 2013). On the other hand, uterine trNK cells are characteristically “super bright” for CD56 and also express high amounts of CD9 and KIRs, neither of which are expressed on most PB CD56 bright cNK cells (Koopman et al, 2003).…”

“…More recently, trNK cell populations have also been described in human BM, spleen, lung, and liver (Aw Yeang et al, 2017; Cuff et al, 2016; Hudspeth et al, 2016; Lugthart et al, 2016; Lunemann et al, 2013; Marquardt et al, 2015; Marquardt et al, 2017; Stegmann et al, 2016). 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).…”

Eomesodermin and T-bet mark developmentally distinct human natural killer cells

“…This Eomes hi population is described as coexpressing CXCR6 and CD69 as markers of tissue residency, with reports differing on whether the Eomes hi cells are more or less cytotoxic than peripheral blood T-bet hi NK cells (18,19,25). A similar CXCR6 + CD69 + population is also described in human lymphoid tissue (26), although the relative expression of Eomes and T-bet was not examined. We therefore examined CXCR6 and CD69 expression in our samples, and found that all Eomes hi NK cells, regardless of tissue or stage, coexpress CXCR6 and CD69 (Figure 3).…”