Disease relevance of Ccr4

• Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset [1].
• CCR4-bearing T cells participate in autoimmune diabetes [2].
• In the present study, we examined the roles of CCL17 and CCL22, two CCR4 ligands, during pulmonary invasive aspergillosis in neutropenic mice [3].
• A major reduction in peribronchial and airway eosinophilia was observed in CCR4-/- mice at all times after conidia challenge in contrast to CCR4+/+ mice [4].
• We conclude that CTACK and CCR4 can both support homing of T cells to skin, and that either one or the other is required for lymphocyte recruitment in cutaneous delayed type hypersensitivity [5].

High impact information on Ccr4

• Here we show that Cnot7(-/-) males are sterile owing to oligo-astheno-teratozoospermia, suggesting that Cnot7, a CCR4-associated transcriptional cofactor, is essential for spermatogenesis [6].
• A cofactor required for infection with virus adapted for growth in transformed T-cell lines was recently identified and named fusin [7].
• Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor [8].
• Expression of the chemokine receptor CCR4 is strongly associated with trafficking of specialized cutaneous memory T helper (Th) lymphocytes to the skin [9].
• We have addressed this issue via competitive bone marrow (BM) reconstitution assays; equal numbers of BM cells from CCR4(+/+) and CCR4(-/-) donors were allowed to develop side-by-side within RAG-1(-/-) hosts [9].

Chemical compound and disease context of Ccr4

• Systemic immunoneutralization of CCL22 from the time of egg injection into S. mansoni-sensitized mice for 8 days significantly decreased CCR4 protein expression, the eosinophil content, the overall size of the egg granuloma, and its hydroxyproline content [10].

Biological context of Ccr4

• Amino acid sequence comparison shows that CHEMR1 is 84% identical to human CCR-4, indicating that CHEMR1 is likely to be a mouse CCR-4 [11].
• Splenocytes and thymocytes isolated from the CCR4(-/-) mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1alpha [12].
• CCR4-deficient mice show prolonged graft survival in a chronic cardiac transplant rejection model [13].
• These findings indicate that CCR4 is involved in the recruitment of NK1.1(+)CD3(+) cells into cardiac allografts and clearly establish an important and novel role for CCR4 in chronic graft rejection [13].
• Furthermore, expression of CCR4 and CCR5, two chemokine receptors implicated in cell adhesion, was found to be downregulated 16 h after infection (2.8 to 4.1 times and 1.9 to 2.8 times, respectively) [14].

Anatomical context of Ccr4

• This may reflect a defect in the ability of the CCR4(-/-) macrophages to be retained in the peritoneal cavity [12].
• Cumulatively, the results demonstrate that CCR4-bearing T cells participate in the development of such tissue-driven autoimmune reactions [2].
• Astrocytes contain mRNA for CCR1, but messages for CCR4 and the orphan chemokine receptor MIP-1alphaR-like#1 were not detected [15].
• Positively selected CD69+CD3intermediate cells gained CCR4, of which ligand, thymus activation-regulated chemokine, was expressed in the medulla [16].
• In brain, however, TCR vaccination did not produce significant changes in chemokine expression but resulted in an increased expression of CCR3 and CCR4 usually associated with Th2 cells [17].

Associations of Ccr4 with chemical compounds

• However, CCR4(-/-) mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4(+/+) mice [12].
• In contrast, in a gallium nitrate chronic cardiac allograft rejection model, cardiac graft survival was significantly prolonged in CCR4(-/-) recipients [13].
• Significant airway hyperresponsiveness to intravenous methacholine was observed at day 3 in CCR4-/- mice, whereas at days 7 and 30, airway hyperresponsiveness was attenuated in these mice compared with control mice [4].

Other interactions of Ccr4

• Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo [1].
• Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells [12].
• Cells expressing the CCR4 ligand TARC (thymus- and activation-regulated chemokine) were detected within infiltrated islets from prediabetic mice [2].
• CCR4 and CCR8 agonists are also likely contributors [18].
• In uninfected mice, IL-4-producing T cells preferentially migrated to the CCR4 ligand, CCL17, whereas IFN-gamma-expressing T cells as well as populations of IL-4+ or IL-10+ T cells migrated to the CXCR3 ligand, CXCL9 [19].

Analytical, diagnostic and therapeutic context of Ccr4

• Analysis of peritoneal lavage cells from CCR4(-/)- mice by flow cytometry also revealed a significant decrease in the F4/80(+) cell population [12].
• To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4(-/-)) mice by gene targeting [12].
• A relative increase in the percentage of graft infiltrating CD8(+) T cells in CCR4(-/-) recipients was observed 30 days after transplantation and was accompanied by a decrease in CD4(+) T cells [13].
• Enzyme-linked immunosorbent assay analysis of whole-lung samples at day 2 after conidial challenge in neutrophil-depleted CCR4-/- and CCR4+/+ mice revealed that whole-lung IL-12 levels were significantly increased in the CCR4-/- group compared with the wild-type group [3].
• By immunohistochemistry, we show that MDC is produced by CNS-infiltrating leukocytes and intraparenchymal microglia, whereas CCR4 is expressed on some invading leukocytes [20].

References