small clusters on chromosomes 1, 2, 5, 7, 9, 10, 16, 17, and 19, mainly subserve homeostatic immune functions. The strongest functional correlate of the four major chemokine groups is receptor specificity: that is, most chemokine receptors bind more than one chemokine but are restricted by group (Table 28.3). With regard to leukocyte specificity, most neutrophil-targeted chemokines are in the CXC group and most of the monocyte-/macrophage-targeted chemokines are in the CC group. Major T and B cell-targeted chemokines can be found in both groups. The leukocyte target specificity of a chemokine may be narrow or broad and is defined by the expression pattern of its cognate receptor(s) (Table 28.4).
peptide antagonists, it is a dimer, in general agreement with previous biochemical data describing ligand-independent CXCR4 dimerization69,70 (Fig. 28.5). Viral GPCRs have been proposed to hijack human receptors such as CXCR4 by heterodimerization.71 Evidence for homo- and heterodimerization has been reported for other chemokine receptors, such as CCR2, CCR5, and CX3CR1, but the precise physiologic forms remain undefined.72,73,74
FIG. 28.2. Chemokine Gene Repertoires in Mouse and Human. Data are from www.ncbi.nlm.nih.gov/genome Builds 37.2 for Homo sapiens and Mus musculus. Brackets pair regions of conserved synteny between the indicated mouse and human chromosomes. Bracket labels denote chemokine groups (see text). Gene names are from the HUGO Gene Nomenclature Committee assignments. Protein names that differ from gene names are given in parentheses. Arrows, gene location and orientation relative to centromere; Mb, megabases; plasma, chemokines found at high concentrations constitutively in plasma. Other codes are in box at lower right. The figure layout is based on a previously published design and helpful advice from Hisayuki Nomiyama of Kumamoto University.
leukocytes. It is an exception to the ligand rule as it binds many, but not all, CC and CXC chemokines.83 DARC mediates transcytosis of chemokines across endothelial cells84 and modulates inflammatory responses.85 CCBP2 is expressed on leukocytes but at low levels. More prominently expressed on placental trophoblasts86 and lymphatic endothelium,87 CCBP2 scavenges inflammatory CC chemokines by a process of rapid internalization and recycling to plasma membrane,88 and affects embryo survival, inflammatory responses, immune activation, and antimicrobial resistance in infection and cancer models.89 One theory is that nonsignaling chemokine binding proteins function as antiinflammatory chemokine buffers, and accordingly they have been referred to as chemokine scavengers, interceptors, and silent or decoy receptors. A third category includes structurally unique broad-spectrum anti-inflammatory chemokine
binding proteins encoded by microbes, including several herpesviruses and poxviruses,90 as well as Schistosoma mansoni91 and ectoparasitic ticks.92
TABLE 28.1 Chemokine Nomenclature
TABLE 28.2 Chemokine Receptor Nomenclature
TABLE 28.3 Chemokine Specificities for Human Seven-Transmembrane Chemokine Receptors
TABLE 28.4 Chemokine Receptor Distribution on Some Hematopoietic Cells
splicing has been reported for several chemokines, but the significance is not well defined. CCL14 and CCL15 are an exceptional example of neighboring genes that give rise to a family of mono- and bicistronic transcripts.109
TABLE 28.5 Sources and Main Immunologic Functions of Human CXC, CX3C, and C Chemokines
inflammatory. Homeostatic chemokines are differentially and constitutively expressed primarily in specific microenvironments of primary and secondary immune organs, and coordinate migration of hematopoietic precursor cells, mature DCs, and naïve and central memory lymphocyte subsets via constitutively expressed receptors.115,116,117,118,119 Inflammatory chemokines are induced by noxious stimuli in tissue cells and leukocytes. Inflammatory chemokine receptors tend to be constitutively expressed on myeloid cells, natural killer (NK) cells, and effector but not naïve lymphocytes.120,121 Dynamic shifts in receptor expression occur during leukocyte differentiation, maturation, and activation.115,122,123,124,125 This is not an absolute classification, because constitutive chemokines may be further induced, and chemokines that are highly inducible in some cell types may be constitutively expressed in others. In addition, there may be differences between mouse and human leukocyte subsets. Table 28.4 condenses a small portion of this vast subject available from the literature. Additional information can be obtained from the Immunologic Genome Project (www.immgen.org), which is a consortium systematically evaluating surface molecule expression in over 250 leukocyte subsets.