Regulation of lymphocyte migration

Migration can be regulated during entry into, transit through and exit from lymphoid and non-lymphoid organs (see Figure 2). The vast majority of studies were and still are concerned with regulation of lymphocyte traffic during entry.

Entry

When lymphocytes enter a lymph node, Peyer's patches or tonsils from the blood, only certain specific sites in the vascular bed are used for migration into the parenchyma. These preferential sites for binding and emigration of lymphocytes are the postcapillary venules in the paracortex, which in most species have a high endothelium. Initially it was assumed that migration into peripheral lymph nodes is mediated by a single molecule on the lymphocytes, called a 'homing receptor', and the corresponding molecule on the HEV, the 'addressin'. Another pair of molecules was thought to be responsible for migration into Peyer's patches. However, it is now clear that a steadily increasing number of receptor pairs exists for the different lymphoid tissues. There is a partly overlapping sequence of interaction of adhesion molecules on lymphocytes and endothelial cells. Some adhesion molecules are expressed consti-tutively and others are inducible by chemokines and cytokines. Lymphocytes are found in the peripheral blood (circulating pool), and also near to or in intermittent contact with the vessel wall (marginal pool; Figure 2, Table 1). The emigration through the vessel wall can be divided into several steps: 1) Lymphocytes make contact with the endothelium and, under appropriate conditions, start to roll on the endothelium, also called tethering. 2) By factors coming

Table 1 Factors influencing lymphocyte entry

Steps during entry

Properties

Implications

Marginal pool (reversible) Adhesion to endothelium (reversible)

Transmigration (irreversible)

Cellular composition Shear force Cell charge

Length of adhesion molecules in relation to other surface molecules e.g. CD45: 300 nm; L-selectin: 30 nm Position of adhesion molecules at the tip of microvilli e.g. L-selectin and a4p7-integrin at the cell base e.g. LFA-1 and CD44 Change of adhesion molecule conformation e.g. LFA-1 within seconds Shedding of adhesion molecules e.g. L-selectin within seconds Release of chemokines Rolling on already adherent neutrophils, lymphocytes, platelets Type of endothelium, e.g. flat or high Site of transmigration, e.g. inter- or intracellular Induction of degrading enzymes, e.g. gelatinase for basal lamina

Determines cell type available for immigration Physical properties important for the availability of adhesion molecules

Mainly involved in the early phase of adhesion

Mainly involved in the late phase of adhesion Facilitates or inhibits adhesion molecule function

Facilitates or inhibits adhesion molecule function

Alters functional state of adhesion molecules Makes adhesion molecules available which are normally not present on the endothelium Selective entry of leukocyte subsets, e.g. normally only lymphocytes but no granulocytes migrate through high endothelium from the endothelial cells or from beneath the basal membrane, lymphocytes become activated, also called triggering, resulting in strong adhesion to the endothelial cell. 3) Finally the lymphocytes start the transmigration, also termed diapedesis. The transmigration is associated with a dramatic change in the morphology of the lymphocytes, e.g. they lose the microvilli on their surface and the cytoplasm forms a uropod. These phases are regulated by different pairs of adhesion molecules, and factors possibly influencing this process are listed in Table 1. A further interesting aspect is the time schedule: lymphocyte activation takes place in a few seconds, strong adhesion in a few minutes but the transmigration lasts several minutes (Figure 2).

The role of adhesion molecules has been elucidated by studies in vitro and in vivo using inhibitory antibodies against adhesion molecules on both lymphocytes and endothelial cells. More recently, experiments in mice deficient in certain adhesion molecules have extended our knowledge about the role of individual molecules in different lymphoid organs. L-Sel-ectin knockout mice, for example, not only show blocking of lymphocyte entry into peripheral lymph nodes (as expected) but also a severe reduction in entry into Peyer's patches. Thus, it has become obvious that one should not speculate on a functional role of an adhesion molecule only based on its pres ence on a cell type. As an example, it has been documented that the adhesion molecule MAdCAM-1, initially thought to be specific for migration into Peyer's patches, is also expressed on cells of the marginal zone of the spleen, but blocking this molecule had no effect on lymphocyte migration into the spleen. So far, no specific molecules have been identified regulating lymphocyte traffic to organs without HEV, such as the spleen, bone marrow, lung and liver.

Recent data showed that some adhesion molecules are concentrated at the tip of the microvilli, whereas others are located at the cell base, indicating different roles in the interaction with the endothelium (Table

1). In addition, adhesion molecules are shed from the cell surface and found as soluble molecules in the serum. The regulatory and potential therapeutic role of these soluble molecules has to be studied in more detail.

Transit and exit

After a lymphocyte has left the blood and migrated via an intercellular route between endothelial cells, the transit through the lymphoid organ starts (Figure

2). Lymphocytes will interact with the extracellular matrix, e.g. with fibronectin, laminin, collagens, and also interstitial cells such as fibrocytes, macrophages and dendritic cells. This transit lasts for hours and enables intercellular contacts and effects of cytokines and chemokines in a paracrine fashion. Very little is known about regulation of the transit through the organs. Finally, most lymphocytes will leave the lymphoid organ again and exit into venules or lymphatics. No regulatory factors have been characterized for this step so far. However, there are indications that this step is carefully regulated. For example, sheep lymphocytes efficiently used the HEVs within pig lymph nodes to exit into the blood, a route normally not taken by sheep lymphocytes. In addition, pig lymphocytes migrated from lymph nodes of fetal lambs into lymphatics, a route not taken by pig lymphocytes but normal for sheep lymphocytes. This suggests that the mechanisms regulating lymphocyte migration are well conserved, at least between these two species which diverged from a common ancestor about 50 million years ago.

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