Disease relevance of Ccr6

• These results indicate that the interaction of CCR6 with its ligand MIP-3alpha contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD [1].
• Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12 [1].
• Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation [2].
• Conversely, in a delayed-type hypersensitivity (DTH) model induced with allogeneic splenocytes, CCR6-/- mice developed no inflammatory response [3].
• In 2,4-dinitrofluorobenzene-induced contact hypersensitivity (CHS) studies, CCR6-/- mice developed more severe and more persistent inflammation than wild-type (WT) animals [3].

High impact information on Ccr6

• Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo [4].
• Remarkably, a defect in CCR6, local neutralization of CCL20, or depletion of monocytes prevents in vivo priming of CD8+ CTL against an innocuous protein antigen administered with adjuvant [4].
• CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches [5].
• CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells [5].
• CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue [6].

Biological context of Ccr6

• However, compared with CA-challenged wild-type mice, challenged CCR6-deficient mice had reduced airway resistance, fewer eosinophils around the airway, lower levels of interleukin 5 in the lung, and reduced serum levels of immunoglobulin E [2].
• These findings underscore the role of CCR6 in cutaneous and intestinal immunity and the utility of CCR6-/- mice as a model to study pathologies in these tissues [3].
• Desensitization of CCR6 on naive B cells with CCL20 resulted in receptor down-regulation and reduced B-cell adhesion [7].
• GvHD incidence was reduced in major histocompatibility complex (MHC) class II-mismatched recipients of CD4+ T cells from CCR6-deficient donors [8].
• PPs of CCR6-/- mice were significantly size-reduced with a proportional loss of B cells and T cells, whereas T-cell subsets were disturbed with a decreased CD4/CD8 ratio paralleled with a loss of regulatory CD4+ CD45Rb(low) T cells [9].

Anatomical context of Ccr6

• However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates [1].
• In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8(+) T lymphocytes, and granulocytes [1].
• Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice [1].
• Early DC recruitment depends in part on CCR2 to traverse vascular endothelium, plus CCR6 to traverse alveolar epithelium [10].
• Here, we demonstrate that in mice lacking the chemokine receptor CCR6, dendritic cells expressing CD11c and CD11b are absent from the subepithelial dome of Peyer's patches [6].

Associations of Ccr6 with chemical compounds

• Attenuation of allergen-induced responses in CCR6-/- mice is dependent upon altered pulmonary T lymphocyte activation [11].
• The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate [12].
• Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain [12].
• However, our reverse transcription-polymerase chain reaction analysis revealed that Ad-infection resulted in the upregulation of the chemokine receptor CCR7 and downregulation of CCR6 in mBM-DCs and LPS-stimulated cells [13].
• In this work, we investigated by flow cytometry the effect of the contact sensitizers 2,4-dinitrofluorobenzene (DNFB), 1,4-phenylenediamine (PPD) and nickel sulfate (NiSO(4)), on the surface expression of the chemokine receptors CCR6 and CXCR4 in DC [14].

Physical interactions of Ccr6

• Macrophage inflammatory protein-3alpha/CCL20 is a recently identified chemokine that binds to CCR6 and acts as a chemoattractant for memory/differentiated T-cells, B-cells, and immature dendritic cells [15].

Regulatory relationships of Ccr6

• CCR6 regulates CD4+ T-cell-mediated acute graft-versus-host disease responses [8].
• Culture of bone marrow precursors from the knock-in mice with GM-CSF for 4 to 6 days led to the appearance of a subset of CD11c(+) DC expressing CCR6 [16].

Other interactions of Ccr6

• The chemokine receptor CCR6 and its ligand MIP-3alpha/CCL20 may be involved in the recruitment of these inflammatory cells [1].
• In contrast, Ab neutralization of CCL9 in vivo resulted in significant reduction of the CD11b(+) DC number in the subepithelial dome regions of Peyer's patches of both wild type and CCR6 -/- mice [17].
• CCR6 mRNA was not detected in any murine DC populations [18].
• The reconstituted response was characterized by an increase in IL-5 levels, eosinophil accumulation, and serum IgE levels in recipient CCR6-/- mice [11].
• CXCR3 and CCR6 transcripts were biased to type-1, and CCR4 transcripts increased in type-1 and type-2 populations [19].

Analytical, diagnostic and therapeutic context of Ccr6

• To elucidate the effect of Mip3alpha on PP lymphocyte development, we used a CCR6/enhanced green fluorescent protein (EGFP) knock-in mouse model and analyzed lymphocyte development by immunohistochemistry and flow cytometry [9].
• To our surprise, using a sensitive immunofluorescence analysis, we observed that CD11b(+) DCs were present in the dome regions of the CCR6-deficient mice [17].
• 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 [20].
• By in situ hybridization, macrophage inflammatory protein (MIP)-3alpha mRNA was dramatically expressed only by the follicle-associated epithelium overlying the SED, while its receptor, CCR6, was concentrated in the SED [21].
• Consistent with these findings, reverse transcriptase polymerase chain reaction analysis and in vitro chemotaxis assays using freshly isolated DCs revealed that CCR6 was functionally expressed only by DC subsets present in the SED, while all subsets expressed functional CCR7 [21].

References