Natural killer cells in liver disease

Abstract

Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including tumor necrosis factor-related apoptosis-inducing ligand-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors through their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis, but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease, but has also revealed new therapeutic targets for managing this disease.

Figure 1. Intrahepatic NK cells in humans

The cell composition of lymphocytes in the human liver is shown. Human liver NK cells include the CD56^bright and CD56^dim subsets. The two subsets exhibit significant differences in their proliferative responses to IL-2, intrinsic cytotoxic capacity, cytokine production, NKR repertoire, and adhesion molecule expression. (1) CD56^bright NK cells expand in response to low doses of IL-2, whereas CD56^dim NK cells respond poorly to IL-2 stimulation. (2) CD56^bright NK cells have a high level of expression of the CD94/ NKG2 C-type lectin receptors and less than 10% of them express KIR. In contrast, more than 85% of the CD56^dim NK cells are KIR⁺ and have a low level of expression of CD94/NKG2. (3) CD56^dim NK cells are more cytotoxic against NK-sensitive targets but produce lower amounts of cytokines than CD56^bright NK cells. (4) CD56^bright NK cells express high levels of CCR7 and CXCR3. (5) Finally, CD56^bright NK cells can be induced from NK cell precursors by IL-15 and may then differentiate into CD56^dim NK cells.

Figure 2. The regulation and functions of liver NK cells. Top panel: The regulation of NK cells

The left side of the top panel illustrates that activated Kupffer cells (KCs), dendritic cells (DCs), and NKT cells can induce NK cell activation via the production of a variety of cytokines. Several cytokines that activate NK cells are also listed. The right side of the top panel illustrates that T regulatory cells and activated HSCs can inhibit NK cell functions via the production of several cytokines. TGF-β is a potent inhibitor of NK cell functions. Bottom panel: The functions of NK cells in the liver. Activated NK cells target hepatocytes, HSCs, and cholangiocytes and perform a variety of important functions in the pathogenesis of liver disease.

Figure 3. The roles of hepatic NK cells in human liver diseases

In a variety of liver diseases, such as viral hepatitis, fatty liver, liver fibrosis, cirrhosis, tumor, and others, significant alterations of hepatic NK cells are observed. NK cells can accumulate within the liver and have higher levels of cytotoxicity and cytokine production, which can be beneficial in inhibiting viral infection, tumor cell growth, and liver fibrosis but can also enhance hepatocellular damage. In addition, chronic liver diseases are associated with a decreased number of NK cells and impairments in NK cell cytotoxicity and cytokine production.