Disease relevance of CCR6

• Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis [1].
• Histiocytes in Rosai-Dorfman disease and hemophagocytic syndrome also coexpressed CCR6 and CCR7, suggesting that this may be a general attribute of abnormal histiocytes [1].
• Involvement of Chemokine Receptor CCR6 in Colorectal Cancer Metastasis [2].
• The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6 [3].
• Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines [4].

High impact information on CCR6

• Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates TLR4 [5].
• Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells [3].
• Thus, beta-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6 [3].
• These immediate precursors expressed CD14, langerin and functional CCR6 [6].
• Immunohistochemical analysis on 13 LCH biopsies of bone, skin, and lymph node all expressed the immature dendritic cell (DC) marker CCR6 on the lesional LCs and absence of the mature DC marker CCR7 [7].

Biological context of CCR6

• Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes [8].
• The observed increase in expression correlated well with the acquisition of an activated/memory phenotype and was largely (CCR5) or completely (CCR6) separated temporally from the initiation of cell division [8].
• Of particular interest is the fact that the enhanced activity on B cells was not associated with an increase in CCR6 expression as assessed by levels of receptor mRNA, surface staining, or MIP-3alpha/CCL20 binding sites, or by a change in the affinity of the receptor for ligand [9].
• In this review, the discovery, the gene and protein structure, the in vitro biological activities, the cell and inducer specific expression and the tissue distribution of CCL20 and CCR6 are discussed [10].
• These data convincingly demonstrate that responses to a chemokine can be regulated solely by changes in the downstream pathways for signal transduction resulting from Ag receptor activation, and establish CCR6 as an efficacious receptor on human B cells [9].

Anatomical context of CCR6

• Expression of CCR6 by pathologic LCs may contribute to their accumulation in nonlymphoid organs such as skin and bone, whereas CCR7 expression may direct them to lymphoid tissue [1].
• Moreover, skin-homing CLA+ memory T cells express high levels of surface CCR6 [11].
• We have shown previously that CCR6 is expressed on peripheral blood B cells, but CCR6 activity on these cells is low in in vitro assays [9].
• The ligand-receptor pair CCL20-CCR6 is responsible for the chemoattraction of immature dendritic cells (DC), effector/memory T-cells and B-cells and plays a role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and rheumatoid arthritis [10].
• Immunohistochemical examination of cryosections of term placental villous tissue confirmed the expression of CCR3, CXCR4, and CCR6 by trophoblast cells [12].

Associations of CCR6 with chemical compounds

• Cytokine-activated PMNLs expressed functional CCR6, as detected by the binding of sodium iodide I 125-labeled liver and activation-regulated chemokine (LARC) and dose-dependent migration toward LARC [13].
• In this report, we have studied the importance of all cysteine residues in the CCR6 sequence using site-directed mutagenesis and biochemical techniques [14].
• CCR6 expression in human HCC tissues was confirmed by RT-PCR [15].
• METHODS AND RESULTS: Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1 [16].

Physical interactions of CCR6

• BACKGROUND: Human CC chemokine Macrophage Inflammatory Protein-3alpha (MIP-3alpha) directs inflammatory cell migration through its binding to the transmembrane receptor CCR6 [17].

Regulatory relationships of CCR6

• LARC induced migration in 293/EBNA-1 cells stably expressing GPR-CY4 with a bi-modal dose-response curve [18].
• CCR6(+) CD8(+) T cells express granzyme A and a low level of perforin but not granzyme B [19].
• Among recombinant cytokines, TNF-alpha induced high levels of CCR6 mRNA expression, whereas interferon (IFN)-gamma induced low levels [13].
• None of the CD34(+)Lin(-) hematopoietic stem cell progenitors or the CD34(+)CD19(+) (pro-B) or the CD19(+)CD10(+) (pre-B/immature B cells) B-cell progenitors expressed CCR6 [20].
• In contrast, IFN-gamma-induced CCR6 loss was irreversible and was concomitant to the induction of DC maturation [21].

Other interactions of CCR6

• Taken together, these findings strongly suggest that CCL20/CCR6 may play a role in the recruitment of T cells to lesional psoriatic skin [11].
• The acquisition of inflammatory chemokine receptors, such as CCR5 and CCR6, may contribute to the efficient relocation of activated T cells to inflamed sites in the periphery [8].
• CC chemokine receptor (CCR) 1 to CCR6 were up-regulated after culture [22].
• The cell surface expression of the chemokine receptors CXCR5 and CCR6 was decreased in SLE patients compared with controls (P = 0.051 and P = 0.002, respectively) [23].
• The reduced CCR6 and CXCR3 expression on PBL correlated with the reduced memory phenotype in circulation and increased memory phenotype in liver [24].

Analytical, diagnostic and therapeutic context of CCR6

• Moreover, flow cytometry phenotype of leukemic PDC (LPDC) revealed an unexpected expression of CCR6 [25].
• By Northern blot analysis, GPR-CY4 mRNA was expressed mainly in spleen, lymph nodes, Appendix, and fetal liver among various human tissues [18].
• By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors [4].
• These data suggest a role for MIP-3alpha/CCL20 in amplification of the immune response during renal allograft rejection by attraction of CCR6+ inflammatory cells, which may include DC, to the site of inflammation [26].
• Bone marrow reconstitution studies demonstrated that ILF development is dependent on CCR6-sufficient B lymphocytes, and adoptive transfers demonstrated that CCR6(-/-) B lymphocytes were inefficient at localizing to intestinal lymphoid structures [27].

References