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160 ParT ONE Principles of Immune Response

TABLE 10.2 CC Chemokines—cont’d
Common Main G Protein– Main Immunological
Chemokine aliases Sources Coupled receptors roles
CCL27 CTACK, Constitutive in placenta, keratinocytes, testis, and brain CCR10 Homing of memory and
Eskine effector T cells to skin
CCL28 MEC Constitutive in epithelial cells of gut, airway CCR10 Homing of T cells to
mucosal surfaces
NA, not applicable; Mo, monocyte; PMN, polymorphonuclear neutrophil; DC, dendritic cell; EC, endothelial cell; HEV, high endothelial venule; MPC, myeloid progenitor cell; plt,
platelet; MΦ, macrophage; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; RANTES, regulated upon activation normal T cell expressed and
secreted; MRP, MIP-related protein; HCC, hemofiltrate CC chemokine; TARC, thymus and activation-related chemokine; PARC, pulmonary and activation-related chemokine; ELC,
Epstein-Barr virus-induced receptor ligand chemokine; LARC, liver and activation-related chemokine; SLC, secondary lymphoid tissue chemokine; MDC, macrophage-derived
chemokine; MPIF, myeloid progenitor inhibitory factor; TECK, thymus-expressed chemokine; CTACK, cutaneous T-cell-associated chemokine; MEC, mucosa-associated epithelial cell
chemokine.

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can occur, and complex quaternary structures bound to glycos- gp120). Secreted chemokine-binding proteins have even been
aminoglycans (GAGs) on the surface of cells may be important identified in tick saliva, which could explain, in part, the lack of
for function in vivo. 1 inflammation associated with tick bites. 7
Chemokine Receptors
Chemokine receptors are defined as mediators that activate cellular KEY CONCEPTS
responses upon binding of chemokines. Twenty-three subtypes Immunological Classification of the
of human chemokine receptors have been identified, all of which Chemokine System
are members of the seven-transmembrane (7TM) domain
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superfamily of receptors. They can be divided into two main • Homeostatic system: Constitutively expressed ligands and receptors.
groups: the G protein–coupled chemotactic chemokine receptors Important in hematopoiesis and immune surveillance. Key receptors:
(n = 19) and the atypical chemokine receptors (n = 4). Chemokine CXCR4 on all leukocytes, especially hematopoietic stem and progenitor
binding, membrane anchoring, and signaling domains for recep- cells; CXCR5 on B cells; CCR7 on dendritic cells and T cells; and
gut and skin-specific T-cell homing receptors CCR9 and CCR10,
tors from both groups come from a single polypeptide chain. respectively.
Structural and biochemical evidence exists that these receptors • Inflammatory system: In innate immunity, inducible ligands and
form homo- and heterodimers. constitutively expressed receptors (e.g., neutrophil CXCR2, monocyte/
Some chemokine receptors pair monogamously with their macrophage CCR2 and CX3CR1, eosinophil CCR3, and NK cell CX3CR1).
chemokine ligands. Most, however, are promiscuous but restricted In adaptive immunity, inducible ligands and inducible receptors (e.g.,
to one chemokine structural group (Fig. 10.2). The G protein– CXCR3, CCR4, and CCR6 on Th1, Th2, and Th17 subsets of CD4 T
coupled receptors are named by ligand group specificity. Each cells, respectively).
chemokine has a unique receptor specificity profile, and each
receptor has a unique chemokine specificity profile. Almost all
chemokines are chemotactic agonists, and a few may be agonists Immunological Classification
at one G protein–coupled chemokine receptor and antagonists Each of the leukocyte subtypes responds to chemokines via a
at another, in addition to binding to atypical receptors. Differential characteristic subset of chemokine receptors. The chemokine
receptor usage, differential regulation of expression, and biased system can be subclassified into two main subsystems, homeostatic
agonism may all account for nonredundant function observed and inflammatory, based on receptor expression patterns.
in vivo for chemokines acting at the same G protein–coupled Homeostatic chemokines are differentially and constitutively
receptor. expressed in specific microenvironments within primary and
secondary immune organs. They recruit both immature and
Atypical Chemokine System Components mature leukocytes via constitutively expressed receptors. Noxious
There are three classes of atypical chemokine system components: stimuli induce inflammatory chemokines in diverse tissue cells
(1) the atypical 7TM chemokine receptors: as described previously, and leukocytes. Inflammatory chemokine receptors are consti-
these bind chemokines promiscuously without signaling or with tutively expressed on myeloid and natural killer (NK) cells but
atypical signaling. These proteins are thought to function as must be induced on activated effector lymphocytes. Dynamic
chemokine scavengers but may also facilitate chemokine trans- shifts in receptor expression occur during dendritic cell (DC)
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cytosis across endothelial barriers; (2) endogenous nonchemokine and NK cell maturation, as well as during lymphocyte maturation,
agonists: these act at chemokine receptors (e.g., β-defensin-2 at activation, and differentiation.
CCR6); (3) virally encoded chemokines, 7TM chemokine recep- Inflammatory CXC and CC chemokine genes are found in
tors, structurally unique chemokine-binding proteins (scavengers), two main clusters on human chromosomes 4q12-q21 and
and nonchemokine chemokine receptor ligands (agonists or 17q11-q21, respectively. Conversely, homeostatic chemokine
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antagonists); examples of the last one include two viral chemokine genes have undergone a diaspora resulting in small clusters of
mimics encoded by HIV: the gp120 and tat proteins, which possess genes on multiple chromosomes. Thirteen of the 19 human
chemokine agonist and antagonist activity, respectively. Viral chemokine receptor genes are clustered at 3p21-23, and CXCR1
chemokine elements can function to evade the immune system, and CXCR2 are adjacent at 2q34-q35. The chemokine and
recruit new target cells, reprogram gene expression for cell chemokine receptor repertoire may vary even among closely
proliferation and angiogenesis, or target cell entry (e.g., HIV related species. Gene copy number (e.g., for CCL3) and sequence