Eomeshi NK Cells in Human Liver Are Long-Lived and Do Not Recirculate but Can Be Replenished from the Circulation

Abstract

Human liver contains an Eomeshi population of NK cells that is not present in the blood. In this study, we show that these cells are characterized by a molecular signature that mediates their retention in the liver. By examining liver transplants where donors and recipients are HLA mismatched, we distinguish between donor liver–derived and recipient-derived leukocytes to show that Eomeslo NK cells circulate freely whereas Eomeshi NK cells are unable to leave the liver. Furthermore, Eomeshi NK cells are retained in the liver for up to 13 y. Therefore, Eomeshi NK cells are long-lived liver-resident cells. We go on to show that Eomeshi NK cells can be recruited from the circulation during adult life and that circulating Eomeslo NK cells are able to upregulate Eomes and molecules mediating liver retention under cytokine conditions similar to those in the liver. This suggests that circulating NK cells are a precursor of their liver-resident counterparts.

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

“…CXCR6+ NK cells showed upregulation of CCR5 which may support their migration toward, and long‐term residence in the liver (Fig. 2c) 18, 29. However CXCR2 and CX3CR1 were reduced, which code for receptors thought to be responsible for the movement of CD56 dim NK cells toward the liver as part of their free movement between compartments (Fig.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Likewise, trNK cells in BM, SLTs, and in the liver are mostly CD94/NKG2A + and NKp46 hi and for the most part lack expression of CD94/NKG2C, KIRs, CD16, and CD57. Interestingly, whereas PB CD56 bright and CD56 dim cNK cells show the same T-BET hi EOMES lo TF profile, trNK cells in multiple different fetal and adult tissues express relatively lower amounts of T-BET and relatively higher amounts of EOMES in comparison to PB cNK cells (Collins et al, 2017; Cuff et al, 2016; Harmon et al, 2016). This T-BET lo EOMES hi profile that is expressed by trNK cells has also been observed among relatively immature CD94 + CD16 − NK cell developmental intermediates (NKDIs) derived in vitro from human CD34 + hematopoietic progenitor cells (HPCs) (Collins et al, 2017).…”

“…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).…”

“…In addition, trNK cells express CCR5, the receptor for CCL3, CCL4, and CCL3L1, as well as CXCR6, the receptor for CXCL16. CD103 (integrin α E ), which binds E-cadherin, is also preferentially expressed by trNK cells in tissues such as MALTs that have an epithelial component (Cuff et al, 2016; Hudspeth et al, 2016; Lugthart et al, 2016; Stegmann et al, 2016). In addition to the above, whereas most PB CD56 bright and CD56 dim cNK cells express CD49e (integrin α 5 ), the absence of this surface protein appears to specifically identify trNK cells, at least in human liver (Aw Yeang et al, 2017).…”

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

“…The liver is also enriched for NK cells, half of which have the CD56 bright phenotype 111. Liver‐resident NK cells have been described to be CD56 bright Eomes high , with high expression of CD69, CXCR6, CCR5,112, 113, 114 with Eomes high cells retained in the human liver without recirculation for up to 13 years 114. Finally, it is known that more than 70% of lymphocytes in the uterine decidua during pregnancy are CD56 bright NK cells,115, 116 expressing adhesion markers such as CD49a, CD69 and CD103.…”