Lymphocyte Recirculation

Lymphocytes are responsible for surveillance of tissue and the immune response to blood-borne microbial agents. To achieve these goals, evolutionary pressures created a bicameral lymph system. Naive and immature lymphocytes circulate only in the blood whereas memory or activated lymphocytes can travel in the blood, leave the circulation, enter the tissues, and return to the blood via the lymph system.

The tissue surveillance mechanism takes advantage of the natural pressure of blood flowing through the system. Extravasation of lymphocytes occurs by movement through plump, cuboidal cells called high endothelial venule cells (HEVs). These cells appear very different from conventional endothelial cells, which have a flat morphology (Fig. 2).

Similar to Velcro adhesive, the HEVs slow and stop, rolling activated lymphocytes. Slowing the rolling lymphocyte entails interactions between L-selec-

Lymphocyte Recirculation

Figure 2. Lymphocyte emigration through the high endothelial venule cells into the tissue. The initial interaction with HEVs in the lymph node is mediated by lymphocyte L-selectin, which interacts with mucin counterreceptors CD34 and glycosylation-depen-dent adhesion molecule 1 (GlyCAM- 1). Increased adhesiveness is mediated by activation of G-protein-coupled receptors. Lymphocyte arrest is mediated by the integrin leukocyte function-associated molecule 1 (LFA-1; also known as aLP2 or CDlla/CD18). The mechanisms involved in transmigration of lymphocytes are unclear, but a coating of glycocalyx on the HEV surface may play a critical role. Modified from Immunology Today, Girard and Springer, 1995b, 16-M9-456, with permission of Elsevier Science.

Figure 2. Lymphocyte emigration through the high endothelial venule cells into the tissue. The initial interaction with HEVs in the lymph node is mediated by lymphocyte L-selectin, which interacts with mucin counterreceptors CD34 and glycosylation-depen-dent adhesion molecule 1 (GlyCAM- 1). Increased adhesiveness is mediated by activation of G-protein-coupled receptors. Lymphocyte arrest is mediated by the integrin leukocyte function-associated molecule 1 (LFA-1; also known as aLP2 or CDlla/CD18). The mechanisms involved in transmigration of lymphocytes are unclear, but a coating of glycocalyx on the HEV surface may play a critical role. Modified from Immunology Today, Girard and Springer, 1995b, 16-M9-456, with permission of Elsevier Science.

tins on the lymphocyte, CD34, and a glycosylation-dependent adhesion molecule (GlyCAM-1) on the HEV. A second signal mediated via G-protein coupled to receptors activates the lymphocyte. It is unclear whether these receptors are ligands for cytokines or other local activation factors.

Arrest of lymphocyte movement requires two separate interactions between the lymphocyte and HEV. Pan lymphocyte integrin molecule LFA-1 (aLP2 or CD1 la/CD18) interacts with the HEV intercellular adhesion molecules 1 and 2 (ICAM-1 and 2). A second lymphocyte integrin called a4 B7 reacts with Mad-CAM-1 on HEVs (Hama, 1994). The latter interactions arrest movement of all memory cells that express high levels of a4 B7.

Passage through the HEVs and into tissue requires remodeling of the HEV junction and the basement membrane. HEVs secrete hevin, a major acidic protein that is rich in cysteine. Hevin reduces the adhesiveness between HEVs. Other molecules such as the hyaluronan receptor (CD44) or the vascular adhesion protein (VAP-1) may- also play a role in the basement membrane remodeling (Jalkanen etal., 1986; Salmi and Jalkanen, 1992; Girard and Springer, 1995b).

The transendothelial passage of lymphocytes is highly efficient and occurs within minutes. Of the lymphocytes circulating in the venules containing HEVs, 25% bind to the latter. Rolling, attachment, and arrest oflymphocytes take only a few seconds. Transepithelial migration occurs in less than 10 min (Smith and Ford, 1983). Approximately 1.4 X 104 lymphocytes can extravasate from a single lymph node every second (Cahill etal., 1976). Along with the cells, the liquid portion of blood is forced into the tissue. Cells, liquids, and any microbial agents traverse the tissue, enter open ended lymphatic vessels, and are transferred to progressively larger vessels. Finally, the cells enter a lymph node.

After passing through the lymph nodes, the cells progress through the lymph system and into the thoracic duct. The duct empties into the subclavian vein near the heart. In this classic pathway of recirculation, approximately 25 X 109 cells per day reach the blood via the thoracic duct. This number represents only 510% of the total lymphocytes (Pabst and Binns, 1989).

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