The T Cell-directed CC Chemokine TARC Is a Highly Specific Biological Ligand for CC Chemokine Receptor 4

Abstract

Chemokines are small secreted polypeptides that play important roles in a wide range of inflammatory and immunological processes by recruiting selected subsets of leukocytes (1, 2). The known chemokines are divided into two major subfamilies based on the spacing of the first two cysteines in the conserved motif. The CXC chemokine subfamily, which includes IL-8 1and IP-10 (4), is characterized by the presence of a single amino acid separating the first two cysteines. The two cysteines are adjacent in the CC chemokine subfamily, which includes RAN-TES (5), MCP-1 (6, 7), MCP-2 (8), MCP-3 (9), MCP-4 (10), MIP-1␣ (11), MIP-1␤ (12), I-309 (13), eotaxin (14, 15), HCC-1 (16), TARC (17), and LARC (18). The CXC chemokines preferentially attract and activate neutrophils, whereas the CC chemokines usually attract and activate monocytes and also basophils, eosinophils, or lymphocytes with variable selectivity (19). Recently, lymphotactin/single C motif 1 that carries only the second and the fourth of the four cysteine residues conserved in other chemokines has been identified, suggesting the existence of the C type chemokine subfamily (20, 21). The human genes for the CXC, CC, and C chemokines are clustered on human chromosomes 4, 17, and 1, respectively (1, 22, 23). Recent studies indicate that genes for certain chemokines are present outside these clusters. For example, a CXC chemokine SDF-1/PBSF has been mapped to human chromosome 10 (24), and CC chemokines TARC and LARC have been mapped to human chromosomes 16 and 2, respectively (18, 25). In addition to chemotactic activity, some chemokines have a regulatory activity on hematopoiesis and angiogenesis (26 -28). Recently, it has been shown that three CC chemokines, MIP-1␣, MIP-1␤, and RANTES, block infection of macrophage-tropic strains of human immunodeficiency virus type 1, while a CXC chemokine, SDF-1/PBSF, blocks infection of T cell line-tropic human immunodeficiency virus type 1 strains (29, 30). The specific effects of chemokines on target cells are mediated by seven-transmembrane G-protein-coupled receptors (31). To date, at least five human CC chemokine receptors have been defined for ligand specificity. CCR1 is a receptor for MIP-1␣, RANTES,; CCR2 is a receptor for 36); CCR3 is a receptor for eotaxin, RANTES,37,38); CCR4 is a receptor for MIP-1␣, RANTES, and MCP-1 (39); and CCR5 is a receptor for MIP-1␣, MIP-1␤, and RANTES (40 -42). The specific ligands for CCR1, CCR2, CCR3, and CCR5 were demonstrated by specific binding and functional assays such as chemotaxis and calcium flux using cDNA-transfected mammalian cells. In the case of CCR4, however, only marginal levels of binding of MIP-1␣ and RANTES were shown with HL-60 cells transfected with CCR4 (43), while a chloride current induction in response to MIP-1␣, RANTES, and MCP-1 was demonstrated in CCR4 cRNA-injected oocytes (39). Except for CCR3 that is almost exclusively expressed on eosinophils (38, 44), other receptors were reported to be expressed on monocytes and lymphocytes. Notably, CCR4 that was originall...

Migration of cytotoxic T lymphocytes toward melanoma cells in three‐dimensional organotypic culture is dependent on CCL2 and CCR4

“…CCR4 binds CCL2, -3, -5, -17 and -22 [26,28]. However, other reports have shown that CCL17 and -22, but not CCL2, -3 and -5 are specific functional ligands for CCR4 [29][30][31]. Thus, CCL2 binding to CCR4, as indicated by our results obtained in the reconstruct (Table 5) and Transwell (Fig.…”

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

“…In our view, CD4 þ T-cells are likely to be recruited from the peripheral blood to lymph nodes infiltrated by classical Hodgkin lymphoma via cytokines such as TARC and RANTES/CCL5 secreted by the Hodgkin-and Reed-Sternberg cells. 16 Interestingly, although only CD4 þ T-cells express CCR4, 17 both CD4 þ T-cells and macrophages express CD4 and CCR5. Although HIV-infected CD4 þ T-cells are eliminated in high numbers, macrophages usually persist as viral reservoirs.…”

CX3C-Chemokine, Fractalkine-Enhanced Adhesion of THP-1 Cells to Endothelial Cells Through Integrin-Dependent and -Independent Mechanisms

“…Northern blots were prepared as described previously (24). Briefly, total RNAs were prepared from various cell lines using Trizol (Life Technologies).…”

“…Briefly, to express fractalkine-SEAP, the DNA fragment encoding fractalkine was amplified from fractalkine cDNA by PCR using 5Ј SalIfractalkine primer (ϩ5Ј-CGCGTCGACTCAGCCATGGCTCCGATA TCT-3Ј) and 3Ј fractalkine-XbaI primer (Ϫ5Ј-CGCTCTAGAGGTGGCT GCCTGGGCGTCAGG-3Ј) and subcloned into pDREF-SEAP (His)6-Hyg vector as described previously (24). CX 3 CSEAP was similarly generated using 5Ј SalI-fractalkine primer and 3Ј fractalkine-XbaI-2 primer (Ϫ5Ј-CGCTCTAGATAGGGCAGCAGCCTGGCGGTC-3Ј).…”

“…Protein concentration was determined by the bicinchoninic acid kit (Pierce, Rockford, IL). The concentration of each recombinant protein was determined by a sandwich-type ELISA as described previously (24).…”