Chemokine Receptors

See also role of Chemokine Receptors in Th1/Th2 development

All known chemokines bind to seven-pass, transmembrane spanning, Gi/Go protin-coupled, Bordetella pertussis toxin sensitive receptors. The complexity of the chemokine system stem from the regulated expression of their receptors. Not only does each chemokine family recruit only specific cell types, the expression of CR is also frequently controlled by regulation according to cell subsets. (e.g., Th1 cells express CCR5 and CSCR3, whereas Th2 cells express CCR3 and CCR4) and or the state of cell activation (e.g., immature DC express CCR1-6, whereas mature DC down-regulated these 6 receptors and upregulate CCR7 expression).

Chemokines Receptors Expressed on DCs:

Circulating DC precursors typically express just two chemokine receptors, CCR2 and CSCR4. Upon entering tissues and differentiating into immature DC, the profile of receptor expression changes. Different immature DC subtypes have been shown to display different patters of receptor expression, but in general these cells express a large number of inflammatory chemokine receptors. These include CCR1, CCR2, CCR5, CCR6, CSCR1, CSCR2, and CSCR4. When these cells are induced to mature, expression (and responsiveness to) inflammatory receptors is gradually lost while expression of a single lymphoid chemokine receptor, CCR7, is rapidly induced. CXCR4 is also up-regulated upon DC maturation.

After capture of Ag in the periphery, DC mature and modulate their chemokine receptor profile, down-regulating CCR1 and CCR5, which recognize RANTES and other proinflammatory chemokines and up-regulating CCR7, which directs cells into the secondary lymphoid tissues.

In general, myeloid DC are thought to follow the classic pattern of DC migration. Evidence suggests that plasmacytoid DC (pDC) enter LN directly from the blood by extravasating across HEV. However, they have also been found to accumulate at some peripheral sites of inflammation.

CCR2: Mice lacking CCR2 display reduced Th1 responses and enhanced Th2 pulmonary responses to inhaled antigen. In contrast, mice lacking MCP-1, one of the CCR2 ligands, display defects in the development of Th2 immune responses. Although other mechanisms may explain these finding, a subset specific defect in DC migration is a possibility. For example, a defect in migration of Langerhans cells to LN has been demonstrated in CCR2 deficient mice.

Like most chemokine receptors, CCR2 is activated by multiple agonists, including MCP-3, MCP-4 and MCP-5. CCR2 knockout mice have significant defects in both delayed type hypersensitivity responses and production of Th1-type cytokines. For example, in response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. Production of IFNγ was also decreased in PPD-sensitized splenocytes from CCR2 knockout mice and in naive splenocytes activate by concanavalin A.

In addition to expression on monocytes and DCs, CCR2 is expressed on activated memory T cells, which raises the possibility that MCP molecuels have direct effects on these cells.

CCR5: Owing to its prominent role as a fusion cofactor for HIV, CCR5 is a major focus of research aiming at determining its structure, biological function and the mechanisms which regulate its signaling and cell surface expression. The predominant role of CCR5 for viral entry and replication is illustrated by the resistance to HIV-1 infection of individuals which lack CCR5 due to a 32 bp deletion in the CCR5 gene. CCR5 is the main coreceptor used by macrophage (M)-tropic strains of HIV-1 and HIV2. A number of inflammatory CC chemokines act as CCR5 agonists. Immature DCs that express CCR5 migrate toward M-tropic CCR5 using HIV-1 which may aid the capture of virions by adhesion molecules of the DC-SIGN family and their presentation to T helper lymphocytes. Chemical antagonists, a number of which have now been developed by several pharmaceutical companies will probably constitute the first set of CCR5 targeted drugs to enter the anti-HIV marketplace.

Targetting CCR5 (via KO or neutralizing mAb) leads to marked improvement of murine cardiac allograft survival that can result in permanent graft acceptance with no chronic rejection when used with cyclosporin (CsA) treatment. CCR5 and the associated chemokines, RANTES, MIP-1α and MIP-1β function in the recruitment of T cells and macrophages into proislet allografts.

CCR5 is expressed on resting T lymphocytes with memory/effector phenotype, monocytes, macrophages and immature DCs and is upregulated by proinflammatory cytokines. It is also present on microglial cells. It is coupled to the Gi class of heterotrimeric G proteins, and inhibits cAMP production, stimulates Ca2+ release and activates PI3 kinase and MAP kinases as well as other tyrosine kinase cascades.

Following induction of the maturation of DCs by LPS or other factors, CCR5 expression is rapidly donregulated in parallel to other receptors of inflammatory chemokines, while CCR7 is upregulated, allowing the attraction of mature DCs to the T cell areas of secondary lymphoid organs.

CCR2 knockout mice have markedly reduced T cell IFNy responses in lymph nodes that drain the antigen exposure sites, diminished type 1 granuloma responses, defects in clearance of intracellular pathogens and increased resistance to the TH1 mediated disease, experimental autoimmune encephalomyelitis (EAE).

CCR6 determines the ability of immature DC to migrate in response to CCL20, its sole ligand.

CCR7:The ligand for CCR7 is CCL19.

CCR8 The ligand for CCR is CCL1. CCR8 is also expressed by eosinophils, Th2 cells, regulatory T cells and skin-homing T cells as well as by monocytes, NK cells, nonhematopoietic cells including endothelial cells and smooth muscle cells.

CXCR1: is the receptor for fractalkine. It has been reported that CXCR1 can serve as a functional co-receptor for HIV-1 and may be involved in the trafficking of lymphocytes in HIV-1/AIDS patients.

CXCR4 determines the ability of immature DC to migrate in response to CXCL12. CXCR4 mediates entry of T cell lines adapted (T-tropic) HIV-1 strains, but not of macrophage tropic (M-tropic) primary isolates and strains that are responsible for virus transmission.

Regulation of Chemokine Receptor Levels:

Chemokine production by DC has consequences not only for recruitment of other cell types, but also for the function of the maturing DC themselves, since it results in triggering and down regulation of the cognate receptors. Triggering of CCR1 and CCr5 may be important to reorganize the actin cytoskeleton and mobilize DC, while their desensitization may allow DC to exit from the inflammatory sites.

The down-regulation of chemokine receptors is known to be mediated through a CCOH-terminal serine-rich domain which is phosphorylated by G-protein-coupled recetpor kinases (GRKs), resulting in receptor internalization by kinases (GRKs), resulting in receptor internalization by interaction with β arrestins. This process results in extinction of the response to the ligand, as well as interference with HIV infection.

DC CCR1 and CCR5 are down regulated within 2 h folowing induction of maturation and this process is prevented by brefeldin A and cycloheximide.