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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: The mechanism for the recruitment and retention of CD8+ T cells within the sinusoids is still unclear. Early studies suggested that activated, but not naive, lymphocytes might be retained in the liver as a result of the exposure of asioglycoconjugates on the surface of these cells, resulting in interactions with the Ashwell–Morel lectin, which is highly expressed on hepatocytes.51 More recent studies have shown that CD8+ T-cell binding to LSECs appears to be independent of the selectin-mediated rolling that is essential for the initial slowing down of T cells from the blood flow in the classical leukocyte adhesion cascade (Figure 1b).4, 52 Rather, it has been found that CD8+ T cells are initially arrested in the liver by binding (via an unknown mechanism) to platelets, which use CD44 to adhere to hyaluronic acid (HA) on LSECs (Figure 1).4 Activated CD8+ T cells appear to be retained within the liver via interactions with ICAM-1 when there is local antigen presentation, while vascular cell adhesion molecule-1 has been implicated in retaining CD8+ T cells in the absence of antigen presentation.7 However, surprisingly other studies have found blockade of β2 integrins, which bind to ICAM-1, does not appear to affect effector CD8+ T cell recruitment to the liver;4 it has also been observed that LFA-1-deficient mice have normal numbers of liver CD8+ T cells.22 Thus, the role of β2 integrins in the retention and residence of CD8+ T cells in the liver is unclear.


The three Rs: Recruitment, Retention and Residence of leukocytes in the liver
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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384287&req=5

fig1: 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.
Mentions: The mechanism for the recruitment and retention of CD8+ T cells within the sinusoids is still unclear. Early studies suggested that activated, but not naive, lymphocytes might be retained in the liver as a result of the exposure of asioglycoconjugates on the surface of these cells, resulting in interactions with the Ashwell–Morel lectin, which is highly expressed on hepatocytes.51 More recent studies have shown that CD8+ T-cell binding to LSECs appears to be independent of the selectin-mediated rolling that is essential for the initial slowing down of T cells from the blood flow in the classical leukocyte adhesion cascade (Figure 1b).4, 52 Rather, it has been found that CD8+ T cells are initially arrested in the liver by binding (via an unknown mechanism) to platelets, which use CD44 to adhere to hyaluronic acid (HA) on LSECs (Figure 1).4 Activated CD8+ T cells appear to be retained within the liver via interactions with ICAM-1 when there is local antigen presentation, while vascular cell adhesion molecule-1 has been implicated in retaining CD8+ T cells in the absence of antigen presentation.7 However, surprisingly other studies have found blockade of β2 integrins, which bind to ICAM-1, does not appear to affect effector CD8+ T cell recruitment to the liver;4 it has also been observed that LFA-1-deficient mice have normal numbers of liver CD8+ T cells.22 Thus, the role of β2 integrins in the retention and residence of CD8+ T cells in the liver is unclear.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus