Liver natural killer cells: subsets and roles in liver immunity

Abstract

The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as 'pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity.

Figure 1

Pit cell in a normal rat liver (Wistar). Organelles are situated on one side of the central nucleus. The other side of the cell is composed of hyaloplasm without organelles. The pit cell makes contact with sinusoidal endothelial cells, and microvilli sometimes protrude into the space of Disse (top left). Pit cells possess characteristic electron-dense granules, in addition to a small number of mitochondria, RER cisternae, and a Golgi apparatus. The pit cell in this figure measures approximately 8 μm in length.

Figure 2

Part of the cytoplasm of a rat liver pit cell at higher magnification, showing the typical structure of the granules. Other organelles in this picture are rod-cored vesicles (smaller than the dense granules and without dense content), mitochondria, a Golgi apparatus, and free ribosomes. A microvesicular body is situated above the Golgi apparatus. The pit cell makes contact with the fenestrated sinusoidal endothelial lining that covers the microvilli of the parenchymal cells, together forming the space of Disse. Original magnification, approximately ×10 000.

Figure 3

One hour after the injection of colon carcinoma cells (CC531) into syngeneic Wagrain rats, a pit cell (left) and a Kupffer cell (lower right) were found attached to a tumor cell (center). Pit cells kill these tumor cells in vitro by secreting perforin and granzyme, causing the apoptosis of the tumor cells. Note that the pit cell granules are assembled at the side facing the tumor cell. The pit cell has not degranulated. It is thought that this secretion triggers membrane changes in the tumor cells, which are recognized by the Kupffer cell and initiate the phagocytic reaction. The first stage in phagocytosis is determined by the attachment of the effector cell to the target cell, which is clearly depicted here. The combination of apoptotic induction (by the pit cell) and phagocytosis (by the Kupffer cell) will kill this tumor cell. The single red blood cell in the sinusoid measures approximately 7 μm.

Figure 4

The adult liver contains two NK cell subsets, cNK cells, and tissue-resident NK cells, the latter of which can develop from liver hematopoietic progenitor cells.