Abstract
AbstractNatural killer (NK) cells comprise one of the most abundant immune cell populations in human liver and the nature and functions of these cells have been a focus of recent interest. Here, we consider the possible roles of NK cells in diverse liver diseases, concentrating on data from patient studies. NK cells can be protective, killing virally infected and cancerous cells in the liver and limiting fibrosis by eliminating hepatic stellate cells. However, they can also be deleterious, contributing to pathology in viral hepatitis by killing hepatocytes and downregulating virus-specific T-cell responses. It has recently emerged that a large fraction of hepatic NK cells constitute a distinct liver-resident subset and we highlight the need to distinguish between circulating and liver-resident NK cells in future studies. There is also a need for further investigation into how NK cells are influenced by the liver microenvironment and what scope there is to harness their immunotherapeutic potential.
Highlights
NK cells were first described as recognising targets that lack MHC class I: the “missing self” response
80 NK cells in the liver NK cells have long been recognised to be extremely abundant in human liver, ordinarily representing between 30% and 50% of liver lymphocytes [6,7,8]
140 A number of studies in mice have shown that chemically-induced liver fibrosis is exacerbated in the absence of NK cells, suggesting that NK cells control fibrosis
Summary
140 A number of studies in mice have shown that chemically-induced liver fibrosis is exacerbated in the absence of NK cells, suggesting that NK cells control fibrosis This is a result of the greater susceptibility of activated hepatic stellate cells to NK cell killing, an effect that may be mediated by their reduced expression of MHC class I [23], increased expression of ligands for NKG2D 145 [24,25], NKp46 [26] or receptors for TRAIL [27], or some combination of these. Patients in the eAg-negative reactivation phase experience temporary increases in viraemia and liver damage, known as “hepatic flares”, associated with increased serum IFNα and IL-8 levels, together with enhanced NK cell activation and TRAIL expression This cytokine combination 200 promotes TRAIL-mediated killing by upregulating TRAIL on NK cells, and altering the balance of death-inducing versus decoy TRAIL receptors on hepatocytes. NK cells are already reaching the clinic for primary and secondary liver cancers and these trials will provide powerful insights into their potential as therapeutic tools. 545
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