Chemokines are a large family of structurally homologous cytokines that within tissues regulate the migration of leukocytes from the blood and lymph into tissues and the movement of leukocytes within tissues. Chemokines stimulate movement of cells along the concentration gradient of the secreted proteins toward their source, a process called chemotaxis (or chemoattraction). The name chemokine is a contraction of chemotactic cytokine. Table 1 summarizes the major features of selected chemokines and their receptors.

Table1. Selected Chemokines and Chemokine Receptors

Chemokine Structure, Production, and Receptors

 Most chemokines are 8- to 10-kD polypeptides that contain two internal disulfide loops and four cysteine residues that are responsible for the tertiary structure. There are 48 human chemokines, which are classified into four families on the basis of the number and location of two of the conserved cysteines. The two major families are the CC (also called β) chemokines, in which the two defining cysteine residues are adjacent, and the CXC (or α) chemokines, in which these residues are separated by one amino acid. In both mice and humans, the genes encoding most of the CC or CXC chemokines are found in distinct clusters on different chromosomes. A few additional chemokines have either a single cysteine (C family) or two cysteines separated by three amino acids (CX3C). There are two structural variants of CXC chemokines, some that have the amino acid sequence glutamic acid-leucine-arginine (called ELR motifs) just before the first cysteine of the CXC motif and others without the ELR motif. CXC chemokines with ELR motifs support neutrophil migration. The other CXC chemokines and the CC chemokines act on monocytes, lymphocytes, and other leukocytes. Chemokines were originally named on the basis of how they were identified and what responses they triggered, but a standard nomenclature has been adopted and coordinated with names for the receptors the chemokines bind to (see Table 1). The CC chemokines are named CCL1 through CCL28, and the CXC chemokines are named CXCL1 through CXCL17.

Chemokines bind tightly to glycosaminoglycans with sulfated N-acetyllactosamine disaccharide repeat units and the binding of different chemokines is determined by the length of the chain of repeats and the pattern of sulfation. These glycosaminoglycans on the surface of endothelial cells or in extra vascular matrices display the bound chemokines to chemokine receptors expressed on circulating cells that have engaged in rolling interactions with endothelial cells.

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, tissue macrophages, fibroblasts, and other stromal cells. In many of these cells, secretion of chemokines is induced by recognition of microbes through various cellular receptors of the innate immune system. In addition, inflammatory cytokines, including TNF, IL-1, and IL-17, induce chemokine production. Several CC chemokines are also produced by activated T cells, providing a link between adaptive immunity and recruitment of inflammatory leukocytes.

The receptors for chemokines belong to the seven-trans membrane, guanosine triphosphate-binding (G) protein coupled receptor (GPCR) superfamily. These receptors initiate intracellular responses through associated trimeric G proteins. All chemokine receptors mediating immune cell migration share an amino acid sequence motif (DRYLAIV) at the end of the third transmembrane domain that is required for interaction with G proteins. The G proteins stimulate signaling events that result in cytoskeletal changes and polymerization of actin and myosin filaments, resulting in increased cell motility. As previously discussed, these signals also increase the affinity of integrins for their ligands.

Different combinations of chemokine receptors are expressed on different types of leukocytes, resulting in distinct patterns of migration of these cells. There are 10 different receptors for CC chemokines (called CCR1 through CCR10), seven for CXC chemokines (called CXCR1 through CXCR6 and CXCR8), one for the C chemokine (called XCR1), and one for CX3CL1 (called CX3CR1; see Table 1). 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. 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 entry of human immunodeficiency virus (HIV) into cells.

A distinct set of chemokine receptors, called atypical chemokine receptors (ACKRs), does not engage heterodimeric G-protein signaling pathways that activate leukocytes but rather is involved in inhibiting or terminating chemokine responses in cells. There are four human ACKRs, expressed on many different cell types, that together bind most of the inflammatory chemokines with high affinity. The signaling capabilities of ACKRs are not well established, but they are involved in transport of chemokines within and across cells (a process called trans cytosis), and they regulate where and how much chemokines are expressed. For example, ACKR1, or DARC (Duffy Antigen Receptor for Chemokines), is found on erythrocytes where it serves to buffer the concentrations of chemokines in the blood. DARC is also found on the specialized endothelium of postcapillary venules (the site of leukocyte migration from the blood into tissues) and mediates transcytosis of some chemokines across the endothelium.

Functions of Chemokines

 Some chemokines are produced by cells in response to external stimuli and are involved in inflammatory reactions. Other chemokines are produced constitutively in tissues and maintain the distribution of cells in these tissues, such as localization of T and B cells in lymphoid organs.

• In inflammatory reactions, chemokines recruit circulating leukocytes from blood vessels into extravascular sites. Different groups of chemokines bind to chemokine receptors expressed on different cells and, in coordination with the types of adhesion molecules expressed, control the nature of the inflammatory infiltrate. Chemokines play two roles in inflammation:

• Increased adhesion of leukocytes to endothelium. Chemokines produced in the tissues bind to heparan sulfate proteoglycans on endothelial cells that line postcapillary venules. The bound chemokines are displayed in this way to circulating leukocytes that are attached to the endothelial surfaces through adhesion molecule interactions. Endothelial display provides a high local concentration of chemokines, enabling them to bind to chemokine receptors on the leukocytes. Signals from chemokine receptors lead to enhanced integrin affinity, which results in firm adhesion of the leukocyte, a critical step for the migration of leukocytes out of blood vessels into extravascular tissue.

• Migration of leukocytes through blood vessels and toward the site of infection or tissue damage. Chemokines produced in the extravascular tissues act on leukocytes that have migrated through the endothelium and exited the circulation. The leukocytes migrate toward infected and damaged cells in tissues, where chemokines are produced and are at the highest concentration.

• Chemokines are involved in the development of lymphoid organs, and they regulate the traffic of lymphocytes and other leukocytes through different regions of secondary lymphoid organs. Because these chemokines are expressed constitutively and maintain normal tissue architecture, they are referred to as homeostatic. Some homeostatic chemokines are also induced under inflammatory conditions and contribute to leukocyte migration out of blood vessels into tissues.

• Chemokines are required for the migration of DCs from sites of infection into draining lymph nodes. DCs are activated by microbes in peripheral tissues and they then migrate to lymph nodes to inform T lymphocytes of the presence of infection. This migration depends on the expression of a chemokine receptor, CCR7, which is induced when the DCs encounter microbes, and chemokines (CCL19 and CCL21) produced in lymphatics and lymphoid tissues that bind to CCR7. Naive T cells also express CCR7 and this explains how DCs and naive T cells localize to the same place in lymph nodes, enabling the DCs to present antigens to the T cells.

Other Chemoattractants and Receptors

Several other types of molecules serve similar functions as chemokines in the immune system, promoting leukocyte migration into inflammatory sites and their directed movement in tissues or maintaining spatial separation of lymphocytes in secondary lymphoid organs. The C3a and C5a complement fragments generated by the activation of complement, the platelet-derived serotonin metabolite 5-hydroxyindoleacetic acid, and the arachidonic acid metabolite leukotriene B4 (LTB4) are important chemoattractants that promote phagocyte migration into tissues during acute inflammatory responses. Other lipid molecules play critical roles in the movement of lymphocytes and DCs in lymph nodes, spleen, and mucosal lymphoid tissues. These include sphingosine 1-phosphate, a lipid required for the egress of lymphocytes out of lymphoid organs, which is discussed later in this chapter, and oxysterols involved in organizing lymphoid follicles and directing the movement of B cells during germinal center reactions. All of these chemoattractant molecules, like chemokines, bind to specific GPCRs expressed on the leukocytes.

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Overview of Humoral and Cell-Mediated Immunity

Fundamental Properties of Adaptive Immune Responses

Colitis, Autoimmunity, and Primary Immunodeficiencies

Hemophagocytic lymphohistiocytosis

Allergic Rhinitis

Mechanisms of Immune Dysregulation in Autoimmune Disease

Chimeric Antigen Receptor T Cells

Checkpoint Inhibition Therapy for Cancer

Mechanisms of Regulation of T-Cell Activation

Neutrophils & Eosinophils Employ Nets to Entrap Parasites

Immunotherapy

Immune Tolerance and Autoimmunity