Migratory routes of lymphocytes

In 1885 Walter Flemming argued that lymphocytes in lymphatics are not only newly formed cells but also lymphocytes on their way back to the blood. It took about 70 years until Gowans provided experimental evidence for lymphocyte traffic from the blood via lymph nodes into the thoracic duct of rats. Since then many studies have documented that similar mechanisms are at work in lymphocyte traffic in all mammals.

The vast majority of lymphocytes migrate from the blood into organs such as the lung, spleen, liver and bone marrow (Figure 1A). They enter the tissues and return into the blood using normal venules and sinusoids. Entry of lymphocytes into the spleen,

Figure 1 Each day about 5 x 1011 lymphocytes leave the blood to migrate into various organs and return into the blood. (A) Most of the blood lymphocytes enter organs such as the lung, spleen, liver and bone marrow via normal venules and sinusoids. The entry is protease-resistant and the lymphocytes have a short residence time in the organs. The vast majority return into the blood via normal venules. Only a few lymphocytes leave these organs via the afferent lymph. (B) In humans about 0.3 x 10" lymphocytes migrate daily from the blood into organs such as the lymph nodes, tonsils and Peyer's patches. They use HEVs, the entry is protease-sensitive and the lymphocytes have a long residence time in the tissue. The lymphocytes return into the blood via the efferent lymph. (C) Only very few lymphocytes migrate under normal circumstances into organs such as the skin, synovia, muscle and brain. They enter these tissues via normal venules and their numbers are only related to blood flow. The lymphocytes return into the blood either via normal venules or via afferent and efferent lymph. However, during acute and chronic inflammation HEV-like structures may develop, leading to a large increase in lymphocyte influx, indicated by the thicker arrows.

which is best understood, seems to be via the marginal zone, and subsequently T and B lymphocytes use different routes through the splenic compartments. The majority leave via the splenic vein and not via lymphatics. On a quantitative basis several-fold more lymphocytes recirculate through the spleen and probably each of the other tissues than through all lymph nodes together. It is often overlooked that the bone marrow and the thymic medulla are included in the normal migratory route of lymphocytes. In addition, nonlymphoid organs, such as the lung and liver, contain large pools of temporarily sessile lymphocytes within the vascular bed, the so-called marginal pool (Figure 2). This is not the result of nonspecific trapping but a specific physiological phenomenon, at least for the lung.

I.ess than 10% of all lymphocytes in the blood migrate into organs such as the lymph nodes, tonsils and Peyer's patches (Figure IB). They use specialized venules, the so-called high endothelial venules (HEV). The lymphocytes return into the blood via the efferent lymph (classic pathway of lymphocyte recirculation). The transit time of lymphocytes from the blood through lymph nodes into the thoracic duct is longer than that through organs not possessing HEVs.

Only very few lymphocytes migrate under normal circumstances into organs such as the skin, synovia, muscle and brain (Figure 1C). They enter these tissues via normal venules and return into the blood either via normal venules or via afferent and efferent lymph. However, during acute and chronic inflammation HEV-like structures may develop, leading to a large increase in lymphocyte influx. The signals involved in the switch from a normal endothelial cell to a specific exit site for lymphocytes are not known.

There appears to be a further area of complexity. In specics like pigs, sheep and calves there are two types of Peyer's patches in the small intestine, which differ in lymphocyte entry from the blood by a factor of up to 10. This heterogeneity has also been found for the different tonsils and lymph nodes and also in the appearance of lymphocyte migration in ontogeny. In addition, it is well-known that within organs, B and T lymphocytes travel differently through the various organ compartments.

The migration described so far is probably indicative of the routes of naive lymphocytes because in most experiments unseparated lymphocyte populations were used which usually contain few activated or memory lymphocytes.

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