expression has been detected in mature dendritic cells (225, 233, 234), naive T-cells, and a subset of memory T-cells (central mem ory T-cells) (235, 236). Two ligands for CCR7 have been identified: MIP-30 (CCL19) and SLC (CCL21) (237). CCR7 and CXCR5 together have been proposed as the main receptors involved in cell recruitment into the lymph nodes, Peyer's patches, and spleen. The constitutive expression of MIP-3/3 (ELC) and SLC in lymphoid tissue supports a role for these chemokines in the trafficking of lymphocytes to secondary lymphoid organs. MIP-3/3 is also expressed in interdigitating dendritic cells, whereas the other ligand for CCR7, SLC, is secreted by stromal cells (238-240). Dieu and colleagues (225) have shown an interesting relationship between CCR6 and CCR7 expression in dendritic cells. Although CCR6 is expressed in immature dendritic cells and these cells are responsive to MIP-3a, cell maturation causes CCR6 downregulation and CCR7 upregulation. Concomitant with the expression of CCR7, mature dendritic cells acquire the capability to respond to MIP-3P. Other studies have also observed CCR7 upregulation in mature dendritic cells (233,234). The differential -expression of these chemo-
kine receptors likely accounts for the distinct migration patterns observed for immature and mature dendritic cells.
A natural mutation in mice, the plt mutation, has helped to elucidate the role of CCR7 and its ligands. Mice homozygous for the mutation show impaired homing of T-cells to the lymph nodes and spleen (241). These mice also show a decreased number of interdigitating dendritic cells in lymph nodes. Recently, the pit mutation has been associated with a deletion that results in the lack of MIP-3/3 and reduced expression of SLC (242). The pheno-type cf pit mice reflects the role of CCR7 in dendritic and T-cell recruitment.
CCR7 knockout mice show a significant reduction in naïve T-cells in secondary lymphoid tissues as well as important lymphoid tissue abnormalities. When challenged, CCR7-/_ mice show an impairment in T-cell-mediated immune response, including impairment of delayed-type hypersensitivity reactions (243). Because of the importance of CCR7 in T- and dendritic-cell recruitment, targeting CCR7 might represent a viable way of interfering with acquired immune responses. However, given that no studies have been reported in which the role of CCR7 has been specifically studied in animal models of human diseases, it is difficult to predict from the in vitro data and the few in vivo studies available, the consequences of inhibiting CCR7.
CCR8 was cloned by several groups as an orphan chemokine receptor (TER1, ChemRl, CKR-L1) (244-246). CCR8 is constitutively expressed at high levels only in the thymus, although low levels of mRNA are also present in the spleen (244).Aligand for human CCR8 has been shown recently to be the CC chemokine 1-309 (CCL1). It was the only chemokine, among a large panel, to induce intracellular calcium mobilization and Chemotaxis in CCR8-transfected cells (247,248).
Both CCR8 and CCR4 are preferentially expressed by Th2 cells (165-167,249) and 1-309 induces a preferential migration of human Th2-polarized cells in vitro (167, 249).
A murine homolog of CCR8 has been characterized and shows a pattern of expression similar to that of hCCR8 (250). In the periph ery, CCR8 mRNA expression was present only in a Th2-polarized subset of CD4+ T-cells. The ligand for mCCR8 has been identified as T-cell activation gene (TCA)-3 (250, 251). TCA-3 induces chemotaxis and activation cf neutrophils, macrophages, mesangial cells, and vascular smooth muscle cells (252-255).
knockout mice have been generated and analyzed in a mouse model of allergic lung inflammation (256). In models of Th2-type response, including Schistosoma mcmso/u-solu-ble egg antigen (SEA)-induced granuloma formation as well as ovalbumin- and cockroach antigen-induced allergic airway inflammation, CCR8 knockout mice showed impaired Th2 cytokine production and reduced eosinophil recruitment. By contrast, in a typical Thl model of secondary granuloma formation, knockout mice behaved in a manner no different from that of wild-type mice. These results suggest an important role for CCR8 in Th2 functional responses in vivo.
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