Leukocyte Circulation and Migration: Functions and Mechanisms
Leukocyte migration into tissues is a crucial aspect of the immune system, governed by specific principles of homing and recruitment through adhesion molecules and chemokines.
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Chapter 3 Leukocyte Circulation and Migration into Tissues
The main functions served by leukocyte migration from blood into tissues A unique property of the immune system is the constant and highly regulated movement of its major cellular components through the blood, into tissues, and often back into the blood again. Leukocyte Homing :The migration of a leukocyte out of the blood and into a particular tissue, or to a site of an infection or injury. The general process of leukocyte movement from blood into tissues is called migration or recruitment. Recirculation: The ability of lymphocytes to repeatedly home to secondary lymphoid organs, reside there transiently, and return to the blood.
Leukocyte homing and recruitment to different tissues are governed by some general principles. Naive lymphocytes continuously migrate mainly into secondary lymphoid organs, whereas effector lymphocytes preferentially home into tissues. Memory lymphocytes migrate into lymphoid organs, mucosal tissues, skin, and other tissues. Leukocyte homing and recruitment require the adhesion of leukocytes to the endothelial lining of postcapillary venules, a process that involves molecules on the surfaces of both the leukocytes (adhesion molecules and chemokine receptors) and endothelial cells (adhesion molecules and chemokines). Endothelial cells at sites of infection and tissue injury are activated by cytokines, resulting in increased expression of adhesion molecules and chemokines.
Adhesion of circulating leukocytes to vascular endothelial cells is mediated by two classes of molecules, called selectins and integrins, and their ligands. P-selectin is stored in cytoplasmic granules of endothelial cells and is redistributed in response to histamine and thrombin. E-selectin is synthesized and expressed on the endothelial cell surface within 1 to 2 hours in response to the IL-1 and TNF in response to infection.
CHEMOKINES AND CHEMOKINE RECEPTORS Chemokines are a large family of cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues. There are 47 human chemokines, which are classified into four families. CC, CXC, C, CX3C.
The chemokines of the CC and CXC subfamilies are produced by leukocytes and by several types of tissue cells, such as endothelial cells, epithelial cells, resident macrophages, fibroblasts, and other stromal cells. Secretion of chemokines is induced by recognition of microbes. In addition, inflammatory cytokines, including TNF, IL-1, and IL-17, induce chemokine production.
Biologic Actions of Chemokines Some chemokines are produced by cells in response to external stimuli. Other chemokines are produced constitutively in tissues and maintain the distribution of cells in these tissues. Essential for the recruitment of circulating leukocytes from blood vessels into extravascular. Increased adhesion of leukocytes to endothelium. Migration of leukocytes through blood vessels and toward the site of infection or tissue damage, chemotaxis (or chemoattraction). Chemokines are involved in the development of lymphoid organs, and they regulate the traffic of lymphocytes and other leukocytes through peripheral lymphoid. Chemokines are required for the migration of dendritic cells from sites of infection into draining lymph nodes.
Multistep leukocyte-endothelial interactions mediating leukocyte recruitment into tissues 1. 2. 3. 4. Selectin-mediated rolling of leukocytes on endothelium Chemokine-mediated increase in affinity of integrins Stable integrin-mediated arrest of leukocytes on endothelium Transmigration of leukocytes through the endothelium.
MIGRATION OF NEUTROPHILS AND MONOCYTES TO SITES OF INFECTION OR TISSUE INJURY Neutrophils are the first type of leukocyte to be recruited from the blood into a site of infection or tissue injury. Monocyte recruitment follows hours later and continues, perhaps for days, after neutrophil recruitment stops. Different migratory behaviors likely reflect variations in relative expression of adhesion molecules and chemokine receptors on neutrophils versus monocytes. Neutrophils express CXCR1 and CXCR2, which bind CXCL1 and CXCL8 (IL-8), the major chemokines that support neutrophil migration into tissues. In contrast to neutrophils, classical monocytes express CCR2. This receptor binds CCL2 (MCP-1).
Pathways of T lymphocyte recirculation If the T cell does not recognize antigen in these sites, it remains naive and leaves the nodes through lymphatics and drains back into the blood stream. Naive T cell repeats its cycle of homing to secondary lymphoid organs. This trafficking pattern of na ve lymphocytes, called lymphocyte recirculation
High endothelial venules Homing of naive T cells into lymph nodes and mucos aassociated lymphoid tissues occurs through the specialized postcapillary high endothelial venules (HEV) that are located in the T cell zones. The endothelial cells of HEVs are specialized to display certain adhesion molecules and chemokines on their surfaces. Naive T cell: L-selectin and LFA-1 and the chemokine receptor CCR7. On lymph node HEVs: GlyCAM-1 and CD34. In Peyer s patches in the intestinal wall: MadCAM-1
Molecules involved in migration of naive and effector T lymphocytes
Memory T Cell Migration Two subsets of memory T cells: central memory and effector memory T cells 1. Central memory T cells: CD45RO+ blood T cells that express high levels of CCR7 and L-selectin. 2. Effector memory T cells: CD45RO+ blood T cells that express low levels of CCR7, L-selectin, and other chemokine receptors. These phenotypes suggest that central memory T cells home to secondary lymphoid organs, whereas effector memory T cells home to peripheral tissues.
