T cell, NK cell, and macrophage recruitment; CTL and NK cell activation
LEUKOCYTE-ENDOTHEUAL iNTERACTiONS AND LEUKOCYTE EXTRAVASATiON 43
Different combinations of more than 17 different chemokine receptors are expressed on different types of leukocytes, which results in distinct patterns of migration of the leukocytes. There are 10 distinct receptors for CC chemokines (called CCR1 through CCR10), six for CXC chemokines (called CXCR1 through CXCR6), and one for CX3CL1 (called CX3CR1) (see Table 3-2). Chemokine receptors are expressed on all leukocytes, with the greatest number and diversity seen on T cells. The receptors exhibit overlapping specificity for chemokines within each family, and the pattern of cellular expression of the receptors determines which cell types respond to which chemokines. Certain chemokine receptors, notably CCR5 and CXCR4, act as coreceptors for the human immunodeficiency virus (HIV) (see Chapter 20). Some activated T lymphocytes secrete chemokines that bind to CCR5 and block infection with HIV by competing with the virus.
Some chemokines are produced by leukocytes and other cells in response to external stimuli and are involved in inflammatory reactions, and other chemokines are produced constitutively in tissues and play a role in tissue organization. Chemokines were discovered on the basis of their activity as leukocyte chemoattractants, and this action is the main basis of their functional roles.
• Chemokines are essential for the recruitment of circulating leukocytes from blood vessels into extravascular sites. Leukocyte recruitment, including naive lymphocytes entering lymph nodes through high endothelial venules and effector lymphocytes, monocytes, and neutrophils entering into tissue sites of infection, is regulated by the actions of several chemokines. Che-mokines produced in the tissues bind to heparan sulfate proteoglycans on endothelial cells that line postcapillary venules and are displayed in this way to circulating leukocytes that have bound to the endo-thelial surfaces through adhesion molecule interactions. The endothelial display provides a high local concentration of chemokines, which bind to chemokine receptors on the leukocytes. Signals from chemo-kine receptors lead to enhanced integrin affinity, which results in firm adhesion of the leukocyte, a critical step for migration of leukocytes out of blood vessels into extravascular tissue. Different chemokines act on different cells and, in coordination with the types of adhesion molecules expressed, thus control the nature of the inflammatory infiltrate.
• Extravascular chemokines stimulate movement of leukocytes and their migration toward the chemical gradient of the secreted protein, a process called che-mokinesis. In this way, leukocytes can be directed toward infected cells in tissues or toward particular regions within lymphoid organs.
• Chemokines are involved in the development of lym-phoid organs, and they regulate the traffic of lymphocytes and other leukocytes through peripheral lymphoid tissues. The function of chemokines in the anatomic organization of lymphoid tissues has been discussed in Chapter 2.
• Chemokines are required for the migration of dendritic cells from sites of infection into draining lymph nodes.
Dendritic cells play a key role in bridging innate and adaptive immunity. They use various receptors to recognize and respond to microbes in peripheral tissues, and they then migrate to lymph nodes to inform T lymphocytes of the presence of infection (discussed in Chapter 6). The migration is dependent on upregula-tion of CCR7 on the dendritic cell in response to recognition of microbes. CCR7 allows the dendritic cell to respond to CCL19 and CCL21, two chemokines that are made in the lymph nodes. Recall that CCR7 is also the chemokine receptor on naive T cells, which explains how dendritic cells and naive T cells localize to the same place in lymph nodes, enabling the dendritic cells to present antigen to the T cells.
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