The three Rs: Recruitment, Retention and Residence of leukocytes in the liver

Abstract

The composition of leukocytes in the liver is highly distinct from that of the blood and lymphoid organs. In particular, the liver is highly enriched in non-conventional T cells such as natural killer T (NKT) cells, γδ T cells and mucosal-associated invariant T cells. In addition, there are significant populations of tissue-resident NK cells (or innate lymphoid cells (ILC1)) and memory CD8⁺ T cells. These cells are joined in conditions of inflammation by neutrophils, monocytes and macrophages. In recent years a multitude of studies have generated insights into how these cells arrest, move and remain resident in the liver. This new understanding has largely been due to the use of intra-vital microscopy to track immune cells in the liver, coupled with gene expression profiling and parabiosis techniques. These studies have revealed that leukocyte recruitment in the liver does not correspond to the classical paradigm of the leukocyte adhesion cascade. Rather, both lymphoid and myeloid cells have been found to adhere in the liver sinusoids in a platelet-dependent manner. Leukocytes have also been observed to patrol the hepatic sinusoids using a characteristic crawling motility. Moreover, T cells have been observed surveying hepatocytes for antigen through the unique fenestrated endothelium of the liver sinusoids, potentially negating the need for extravasation. In this review we highlight some of these recent discoveries and examine the different molecular interactions required for the recruitment, retention and-in some cases-residence of diverse leukocyte populations within the liver.

Figure 1

Lymphocytes within the sinusoidal microenvironment. The sinusoids are lined by specialized liver sinusoidal endothelial cells (LSEC), which are fenestrated and allow interactions to occur between lymphocytes in the sinusoidal blood and hepatocytes. The largest subsets of lymphocytes within the liver are NKT cells and CD8⁺ T cells, which both migrate along the luminal surface of LSECs independent of the blood flow. NKT cells are retained within the liver via LFA-1:ICAM-1 interactions (a), whereas CD8⁺ T cells are initially captured from circulation via platelets (b; HA, hyaluronic acid) and interact with a variety of adhesion molecules on LSECs. Other liver resident cells include Kupffer macrophages, which are primarily situated on LSECs in the sinusoids, and hepatic stellate cells that reside within the space of Disse.

Figure 2

Migration of myeloid populations in the liver following sterile injury. (a) In a well-established model of sterile injury a small, defined inflammatory focus can be induced by thermal injury. (b) Platelets are then recruited that pave the fenestrated endothelium to allow the migration of neutrophils; these neutrophils that initially follow a CXCL2 gradient to the edge of the site of injury and are subsequently recruited into the site of injury following a N-formyl peptide gradient. (c) CCR2⁺ monocytes also display patrolling behavior in the sinusoids and require CCR2 to enter the site of necrosis. (d) Having entered the site of injury CCR2⁺ monocytes are observed to upregulate CX3CR1 potentially to facilitate tissue repair. (e) F4/80 macrophages from the peritoneal cavity can also migrate in a CD44-dependent manner into the liver.