Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology

Abstract

The liver is considered a preferential tissue for NK cells residency. In humans, almost 50% of all intrahepatic lymphocytes are NK cells that are strongly imprinted in a liver-specific manner and show a broad spectrum of cellular heterogeneity. Hepatic NK (he-NK) cells play key roles in tuning liver immune response in both physiological and pathological conditions. Therefore, there is a pressing need to comprehensively characterize human he-NK cells to better understand the related mechanisms regulating their effector-functions within the dynamic balance between immune-tolerance and immune-surveillance. This is of particular relevance in the liver that is the only solid organ whose parenchyma is constantly challenged on daily basis by millions of foreign antigens drained from the gut. Therefore, the present review summarizes our current knowledge on he-NK cells in the light of the latest discoveries in the field of NK cell biology and clinical relevance.

Keywords: Natural Kill cell; homeostais; homeostasis; liver; tissue immunity.

Figure 1

Human hepatic and conventional NK cell subsets, distribution, and phenotype. Human blood circulating conventional NK (cNK) cells contain two main subsets: CD56^dim (cNK^dim) and CD56^bright (cNK^bright) cells. Human hepatic NK (he-NK) cell compartment contains: liver resident NK (lr-NK) cells, memory-like NK (ml-NK) cells and transient conventional NK (cNK) cells mainly represented by recirculating cNK^dim cells through the liver blood system (gray arrow). Lr-NK and ml-NK cell subsets show transcriptional and phenotypic differences compared to the conventional cNK cell subsets.

Figure 2

Involvement of he-NK cells in the maintenance of hepatic tolerance and homeostasis. NK cells promote hepatic tolerance by interplaying with hepatocytes via CD94/NKG2A that in a TGF-β-mediated manner modulate DCs that further prompt expansion of tolerogenic CD4^posCD25^pos Treg cells. On the other hand, Treg cells along with hepatic KCs and apoptotic cells contribute to the production of immunosuppressive factors IL-10 and TGF-β that can induce tolerogenic he-NK cells. Green arrows show stimulatory connection and red lines inhibition.

Figure 3

Dichotomy in the he-NK cell response in tumor and viral infection. Different soluble factors and cell surface receptors contribute to positive or either negative he-NK cell response in both tumor and/or viral infection. Increased (vertical blue arrows) frequency and effector-functions of he-NK cells were observed in early tumor and acute viral response. On the other hand, NK cell dysfunction (vertical red arrows) in late tumor or chronic infection results with lower NK cells frequency, effector function inhibition and cell exhaustion. Arched green arrows show stimulatory connection and red lines inhibition.