Human liver-derived CXCR6+ NK cells are predominantly educated through NKG2A and show reduced cytokine production

Abstract

NK cells have been implicated to affect the outcome of numerous liver diseases. In particular, members of the killer‐cell Ig‐like receptor (KIR) family, predominantly expressed by NK cells, have been associated with the outcome of hepatitis C virus infection and clearance of hepatocellular carcinoma. Inhibitory KIRs tune NK cell function through interaction with HLA class I, a process termed education. Nevertheless, the impact of the hepatic environment on NK cell education is incompletely understood. Therefore, we investigated the composition and function of hepatic KIR‐expressing NK cells. Matched PBMC and hepatic lymphocytes were isolated from 20 individuals undergoing liver surgery and subsequently phenotypically analyzed for expression of KIRs and markers for tissue residency using flow cytometry. NK cell function was determined by co‐culturing NK cells with the target cell line 721.221 and subsequent assessment of CD107a, IFN‐γ, and TNF‐α expression. Liver‐resident CXCR6+/CD56Bright NK cells lacked KIRs and were predominantly educated through NKG2A, while CXCR6−/CD16+ NK cells expressed KIRs and resembled peripheral blood NK cells. Hepatic NK cells showed lower response rates compared to peripheral blood NK cells; in particular, CXCR6+ NK cells were hyporesponsive to stimulation with target cells. The high proportion of educated NK cells in both subsets indicates the importance of self‐inhibitory receptors for the balance between maintenance of self‐tolerance and functional readiness. However, the reduced functionality of hepatic NK cells may reflect the impact of the tolerogenic hepatic environment on NK cells irrespective of NK cell education.

Antigens of Mycobacterium tuberculosis Stimulate CXCR6+ Natural Killer Cells

“…Indeed, higher percentages of circulating CXCR6+ NK cells were observed in three (∼18%) ATB patients (Figure 2E). CD49a identifies another subset of human intrahepatic NK cells that produce high levels of cytokines upon stimulation (16,19). Although this subset is almost undetectable in peripheral blood, we found high percentages of NK cells with the phenotype CXCR6-CD49a+ in two HD (20%), three LTBI individuals (30%), and six ATB patients (35%), with no differences between groups, indicating that this population of NK cells are not relevant for TB ( Supplementary Figure 2).…”

Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy

“…dNK are phenotypically and functionally unlike other trNK present in many human tissues 9 . CD49a+liver-resident NK cells (lrNK) express KIR but not NKG2A, whilst CXCR6+lrNK express NKG2A and not KIR [51][52][53] . The main lung NK cells are circulating CD56 dim CD16+, with a smaller CD56 bright NK population expressing CD69, CD49a, and CD103 54,55 .…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…44 Furthermore, liver-resident CXCR6 + CD56 bright NK cells are predominantly educated via NKG2A, since these cells generally lack the expression of self-inhibitory KIRs. 46 NKp80 was reported as another phenotypic marker of human NK cells that is not expressed on ILC1s. 47 The chemoattractant receptor expressed on Th2 cells (CRTH2) is selectively expressed on ILC2s, and in the human liver, the ILC population (CD45 + Lin − CD127 + CD16 − NKG2A − ) can be divided into distinct subsets: ILC1 (CD117 − NKp44 − CRTH2 − ), ILC2 (CRTH2 + ) and ILC3 (CD117 + CRTH2 − ) cells; and two subsets, NKp44 − ILC3 and NKp44 + ILC3, defined according to NKp44 expression.…”

“…In the human liver, resident CXCR6 + /CD56 bright NK cells are predominantly educated through NKG2A and are hyporesponsive to stimulation by target cells with reduced cytokine production, indicating that novel management aimed at activating LrNK cells could be beneficial in the control of infections or cancer. 46 NKG2A expression was influenced by factors from cancer nests, such as a high level of IL-10 in HCC patients, and contributed to NK cell exhaustion, suggesting that blockade of NKG2A has the potential to restore immune surveillance on liver tumors by reversing NK cell exhaustion. 175 Additionally, inhibition of NKG2A signaling on NK/ILC1s can induce robust immune responses of CD8 + T cells against persistent pathogens in the liver as a novel vaccine strategy.…”