GO:0031731 CCR6 chemokine receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031731 (CCR6 chemokine receptor binding) is a molecular function defined as binding to a CCR6 chemokine receptor.
• The principal endogenous ligand for CCR6 is CCL20 (also known as LARC/MIP-3alpha), and the interaction is structurally resolved.
• CCR6-CCL20 binding controls recruitment of Th17 cells, regulatory T cells, dendritic cells, and innate lymphoid cells to mucosal and inflamed tissues.
• The CCR6-CCL20 axis is implicated in chronic pancreatitis, colorectal cancer liver metastasis, skin inflammation, allergic asthma, and neuroinflammation.
• Small-molecule CCR6 antagonists such as PF-07054894 can distinguish CCR6 from homologous chemokine receptors and reduce IL-23-driven skin inflammation.
• CRISPR-based knockout, knock-in, and overexpression models enable causal testing of CCR6 ligand-receptor interactions in immune and cancer biology.
Description
GO:0031731, CCR6 chemokine receptor binding, is a molecular function term in the Gene Ontology that describes the binding of a ligand to the CCR6 chemokine receptor. CCR6 is a C-C chemokine receptor that is expressed on subsets of T cells, dendritic cells, and innate lymphoid cells, and its principal endogenous protein ligand is CCL20 (also called LARC or MIP-3alpha). The interaction between CCL20 and CCR6 is a key checkpoint for directing leukocyte migration to mucosal surfaces and inflamed tissues. Because this binding event initiates downstream signaling that shapes immune microenvironments, it is a focal point for research in immunology, oncology, and inflammatory disease. Researchers study CCR6 chemokine receptor binding to understand how chemokine gradients are interpreted by immune cells and how dysregulated ligand-receptor interactions contribute to disease. For example, single-cell sequencing of human chronic pancreatitis has revealed distinct immune microenvironments driven by CCR6-CCL20 crosstalk. In colorectal cancer, extracellular vesicles carrying miR-181a-5p promote liver metastasis by activating hepatic stellate cells and remodeling the tumor microenvironment, a process linked to CCR6-CCL20 signaling. Pharmacological blockade of CCR6 with the antagonist PF-07054894 increases basal circulating CCR6+ T cells and ameliorates IL-23-induced skin inflammation, demonstrating the therapeutic relevance of this binding event. This article provides a research-grade overview of GO:0031731, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental methods including CRISPR-based models. All factual statements are supported by published literature cited by number-.
CCR6 chemokine receptor binding At A Glance
| GO ID | GO:0031731 |
|---|---|
| GO term | CCR6 chemokine receptor binding |
| Ontology | molecular_function |
| Synonym | CCR6 chemokine receptor ligand; LARC receptor binding |
| Major function | Binding to the CCR6 chemokine receptor, typically by CCL20, to initiate chemotaxis and immune cell recruitment |
| Principal ligand | CCL20 (LARC/MIP-3alpha) |
| Receptor | CCR6 (C-C chemokine receptor type 6) |
| Associated cells | Th17 cells, regulatory T cells, dendritic cells, innate lymphoid cells |
| Disease relevance | Chronic pancreatitis, colorectal cancer metastasis, skin inflammation, allergic asthma, neuroinflammation |
What Is GO:0031731?
According to the Gene Ontology, GO:0031731 (CCR6 chemokine receptor binding) is defined as the binding to a CCR6 chemokine receptor. In other words, it is the molecular function exerted by a ligand when it physically interacts with the CCR6 receptor protein. The term is classified under molecular_function and has synonyms including CCR6 chemokine receptor ligand and LARC receptor binding. This function is typically mediated by chemokines such as CCL20, which binds CCR6 with high specificity and triggers receptor activation.
Why Is CCR6 chemokine receptor binding Important in Cell Biology?
CCR6 chemokine receptor binding is critically important because it governs the directed migration of immune cells to mucosal and inflamed tissues, thereby shaping host defense and tissue homeostasis. Dysregulation of this binding event is associated with a wide range of human diseases, including chronic inflammatory conditions, cancer metastasis, and allergic asthma. Understanding the molecular details of CCR6-CCL20 interaction provides a rational basis for developing therapeutics that modulate immune cell trafficking, as exemplified by CCR6 antagonists that ameliorate skin inflammation.
• Controls recruitment of Th17 cells and regulatory T cells to mucosal sites, influencing immune tolerance and inflammation.
• Mediates crosstalk between immune cells and stromal cells in chronic pancreatitis, contributing to disease pathogenesis.
• Promotes liver metastasis in colorectal cancer by activating hepatic stellate cells and remodeling the tumor microenvironment.
• Is a validated target for anti-inflammatory therapy, as CCR6 antagonists reduce IL-23-induced skin inflammation.
• Regulates monocyte recruitment in allergic asthma through ciliated cell-derived IL-17D.
• Contributes to neuroinflammation by promoting CCR6 expression on Th17 cells.
• Serves as a biomarker for distinct immune microenvironments in human disease.
• Enables experimental dissection of chemokine gradients using CRISPR knockout and knock-in models.
• Provides structural insights for rational drug design targeting CCR6.
• Links innate and adaptive immunity through innate lymphoid cell recruitment.
Molecular Mechanism of CCR6 chemokine receptor binding
Ligand Recognition and Binding Specificity
In simple terms: CCL20 fits into a pocket on CCR6 like a key in a lock, but only CCR6 has the right shape.
The endogenous protein ligand CCL20 binds to CCR6 with high specificity, distinguishing it from homologous chemokine receptors. Structural studies have resolved the basis for CCR6 activation by CCL20, revealing key interaction surfaces that confer selectivity. This binding event is the first step in receptor activation and is required for downstream signaling.
Receptor Activation and Conformational Changes
In simple terms: Once CCL20 binds, CCR6 changes shape to send a signal inside the cell.
Binding of CCL20 to CCR6 induces conformational changes in the receptor that lead to G-protein activation and downstream signaling. This activation triggers chemotaxis and integrin-mediated adhesion, enabling cell migration. The structural basis for CCR6 activation by CCL20 has been elucidated, providing a framework for understanding how antagonists block this process.
Regulation by RNA-Binding Proteins
In simple terms: A protein called HuR helps stabilize the instructions for making CCR6, increasing its levels on Th17 cells.
The RNA-binding protein HuR contributes to neuroinflammation by promoting CCR6 expression on Th17 cells. This post-transcriptional regulation increases the availability of CCR6 on the cell surface, enhancing responsiveness to CCL20. Thus, CCR6 chemokine receptor binding is modulated not only by ligand availability but also by the abundance of the receptor itself.
Pharmacological Modulation
In simple terms: Drugs can block CCR6 to stop immune cells from moving into inflamed tissues.
The small-molecule CCR6 antagonist PF-07054894 distinguishes between homologous chemokine receptors, increases basal circulating CCR6+ T cells, and ameliorates IL-23-induced skin inflammation. This demonstrates that pharmacological interference with CCR6 chemokine receptor binding can modulate immune cell trafficking in vivo. Such antagonists provide tools to dissect the contribution of CCR6-CCL20 interactions to disease.
Role in Immune Cell Recruitment
In simple terms: CCR6 binding tells immune cells where to go, like a GPS signal.
CCR6-CCL20 crosstalk directs the recruitment of Th17 cells, regulatory T cells, dendritic cells, and innate lymphoid cells to mucosal and inflamed tissues. In the intestine, a feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier through CCR6-dependent mechanisms. In chronic pancreatitis, single-cell sequencing has unveiled distinct immune microenvironments shaped by CCR6-CCL20 interactions.
Key Genes Involved in GO:0031731 CCR6 chemokine receptor binding
The following genes and proteins are central to CCR6 chemokine receptor binding and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCR6 | Receptor for CCL20; mediates chemotaxis of immune cells | Target for antagonists; knockout models to study immune cell trafficking |
| CCL20 | Endogenous ligand for CCR6; activates receptor signaling | Knockout or overexpression to modulate CCR6-dependent recruitment |
| IL17D | Ciliated cell-derived cytokine that restrains allergic asthma via monocyte recruitment | Model to study CCR6-dependent monocyte recruitment in asthma |
| IL23 | Cytokine that induces skin inflammation; used to model CCR6 antagonist effects | In vivo model for testing CCR6 antagonists |
| HuR (ELAVL1) | RNA-binding protein that stabilizes CCR6 mRNA and promotes expression on Th17 cells | Knockdown or knockout to study post-transcriptional regulation of CCR6 |
| TCF1 (TCF7) | Transcription factor marking progenitor CD8 T cells; linked to antigen dominance hierarchies | Model to study T cell phenotypes in tumors |
| RORγt (RORC) | Transcription factor for Th17 cells; co-expressed with CCR6 | Knockout to study Th17 differentiation and CCR6 expression |
| FOXP3 | Regulatory T cell marker; CCR6+ Tregs migrate to inflamed tissues | Model to study Treg recruitment |
| CD4 | T cell co-receptor; defines Th17 and Treg subsets expressing CCR6 | Flow cytometry and functional assays |
| CD8 | T cell co-receptor; CCR6 expression on subsets | Tumor immunology models |
| ILC3 | Innate lymphoid cells that respond to CCR6-CCL20 signals in intestine | Knockout models to study intestinal barrier |
| Dendritic cells (CD11c+) | Antigen-presenting cells that migrate via CCR6 | Tracking studies in inflammation |
| Hepatic stellate cells | Activated by extracellular vesicles in colorectal cancer metastasis | Co-culture models for liver metastasis |
| miR-181a-5p | MicroRNA in extracellular vesicles that promotes liver metastasis | Overexpression or inhibition in cancer models |
| PF-07054894 (drug) | Small-molecule CCR6 antagonist | Pharmacological tool for in vivo studies |
| CCL20+ epithelial cells | Source of CCL20 in mucosal tissues | Conditional knockout or reporter models |
| Th17 cells | CCR6+ effector T cells that produce IL-17 | Adoptive transfer and knockout models |
| Tregs | CCR6+ regulatory T cells that suppress inflammation | Depletion or expansion models |
How Is CCR6 chemokine receptor binding Regulated?
CCR6 chemokine receptor binding is regulated at multiple levels. Post-transcriptionally, the RNA-binding protein HuR promotes CCR6 expression on Th17 cells, thereby increasing the availability of receptor for CCL20 binding and contributing to neuroinflammation. At the ligand level, CCL20 expression is induced by inflammatory cytokines such as IL-23, which drives skin inflammation and is used experimentally to model CCR6-dependent pathology. In the intestine, a feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier through CCR6-CCL20 interactions, indicating that nutritional status can modulate this axis. Pharmacological antagonists such as PF-07054894 can block CCR6 binding and increase basal circulating CCR6+ T cells, demonstrating that the axis is dynamically regulated in vivo.
CCR6 chemokine receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCR6 | Chronic pancreatitis, skin inflammation | Knockout mice, antagonist treatment |
| CCL20 | Colorectal cancer liver metastasis | Overexpression in cancer cells, co-culture with stellate cells |
| IL17D | Allergic asthma | Ciliated cell-specific knockout |
| HuR (ELAVL1) | Neuroinflammation | Th17-specific knockout or knockdown |
| IL23 | Skin inflammation | IL-23 injection model in mice |
Chronic Pancreatitis
Single-cell sequencing of human chronic pancreatitis has unveiled distinct immune microenvironments with CCR6-CCL20 crosstalk. This crosstalk likely contributes to the recruitment of immune cells that drive fibrosis and inflammation in the pancreas. Targeting CCR6-CCL20 interactions may therefore offer a therapeutic strategy for chronic pancreatitis.
Colorectal Cancer Metastasis
Highly metastatic colorectal cancer cells release miR-181a-5p-rich extracellular vesicles that promote liver metastasis by activating hepatic stellate cells and remodeling the tumor microenvironment. This process is linked to CCR6-CCL20 signaling, suggesting that CCR6 chemokine receptor binding facilitates the metastatic niche. Inhibiting this interaction could reduce liver metastasis.
Skin Inflammation
The CCR6 antagonist PF-07054894 ameliorates IL-23-induced skin inflammation, demonstrating that CCR6 chemokine receptor binding is a driver of inflammatory skin disease. This antagonist distinguishes between homologous chemokine receptors and increases basal circulating CCR6+ T cells. These findings support CCR6 as a therapeutic target in psoriasis-like inflammation.
Allergic Asthma and Neuroinflammation
Ciliated cell-derived IL-17D restrains allergic asthma through controlling monocyte recruitment, a process that may involve CCR6-dependent mechanisms. In neuroinflammation, HuR promotes CCR6 expression on Th17 cells, enhancing their pathogenicity in the central nervous system. Thus, CCR6 chemokine receptor binding contributes to both airway and neurological inflammatory diseases.
From CCR6 chemokine receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CCR6 mediate Th17 recruitment to inflamed skin? | CCR6 knockout mouse with IL-23-induced dermatitis |
| What is the role of CCL20 in liver metastasis? | CCL20 knockout colorectal cancer cells in liver metastasis assay |
| How does HuR regulate CCR6 expression? | HuR knockout or knockdown in Th17 cells |
| Can a CCR6 antagonist reduce allergic asthma? | House dust mite-induced asthma model treated with PF-07054894 |
| What is the structural basis of CCL20-CCR6 binding? | Recombinant CCR6 and CCL20 for cryo-EM or X-ray crystallography |
| Does CCR6-CCL20 crosstalk shape the pancreatic immune microenvironment? | Single-cell RNA-seq of human chronic pancreatitis samples |
How to Study the CCR6 chemokine receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Single-cell RNA-seq | Gene expression at single-cell resolution | Immune microenvironment profiling in chronic pancreatitis |
| Flow cytometry | Surface CCR6 expression on immune cells | Tracking CCR6+ T cell subsets in blood and tissues |
| Cryo-EM/X-ray crystallography | Three-dimensional structure of CCR6-CCL20 complex | Structure-guided drug design |
| Extracellular vesicle isolation | miRNA content and functional effects | Cancer metastasis research |
| Immunohistochemistry | Tissue localization of CCR6 and CCL20 | Pathology studies |
| ELISA | CCL20 concentration in serum or supernatants | Inflammation biomarker measurement |
| CRISPR knockout | Loss-of-function effects on CCR6 binding | Causal gene validation |
| Reporter assays | CCR6 promoter activity or signaling | Regulation of CCR6 expression |
Single-Cell Sequencing
Single-cell RNA sequencing has been used to unveil distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis. This method allows researchers to identify which cell types express CCR6 and CCL20 and how they interact in disease. It is particularly useful for discovering novel therapeutic targets within the CCR6 axis.
Flow Cytometry and Immunophenotyping
Flow cytometry is used to quantify CCR6+ T cell subsets, including Th17 and regulatory T cells, in blood and tissues. The CCR6 antagonist PF-07054894 increases basal circulating CCR6+ T cells, which can be monitored by flow cytometry. This method is essential for tracking immune cell trafficking in vivo.
Structural Biology
Structural studies have resolved the basis for CCR6 activation by the endogenous protein ligand CCL20. Techniques such as cryo-electron microscopy or X-ray crystallography provide atomic-level details of the binding interface. These insights guide the design of small-molecule antagonists like PF-07054894.
Extracellular Vesicle Analysis
Highly metastatic colorectal cancer cells release miR-181a-5p-rich extracellular vesicles that promote liver metastasis. Researchers use vesicle isolation and miRNA profiling to study how these vesicles activate hepatic stellate cells and remodel the tumor microenvironment. This method links CCR6-CCL20 signaling to cancer progression.
How CRISPR Can Be Used to Study GO:0031731 CCR6 chemokine receptor binding
Knockout
CRISPR knockout of CCR6 or CCL20 in cell lines and mouse models enables causal testing of their role in immune cell recruitment and disease. For example, CCR6 knockout mice can be used to study IL-23-induced skin inflammation and allergic asthma. Knockout of HuR in Th17 cells can reveal its contribution to CCR6 expression and neuroinflammation.
Point Mutation
Point mutations in the CCR6 ligand-binding pocket can be introduced to dissect the structural determinants of CCL20 binding. Such models help distinguish between binding affinity and downstream signaling. They are valuable for validating structural predictions from cryo-EM studies.
Knock-in
Knock-in of tagged CCR6 (e.g., fluorescent or epitope tags) allows real-time tracking of receptor localization and trafficking in live cells. Knock-in of disease-associated variants can model human genetic susceptibility. This approach is useful for studying CCR6 dynamics in chronic pancreatitis and cancer.
Overexpression
Overexpression of CCL20 or CCR6 in cancer cells or immune cells can enhance CCR6 chemokine receptor binding and promote metastasis or inflammation. For instance, overexpression of miR-181a-5p in colorectal cancer cells increases extracellular vesicle release and liver metastasis. Overexpression models are useful for gain-of-function studies.
How EDITGENE Supports CCR6 chemokine receptor binding Research
Researchers studying CCR6 chemokine receptor binding-related genes often need to determine whether a candidate gene is causally involved in immune cell recruitment, inflammation, or cancer metastasis. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such investigations, from knockout to knock-in and overexpression models, as well as library screening and bioinformatics support.
Contact EDITGENE today to design your custom CRISPR model for CCR6 chemokine receptor binding research.
Frequently Asked Questions About CCR6 chemokine receptor binding
What is GO:0031731?
GO:0031731 is the Gene Ontology term for CCR6 chemokine receptor binding, defined as binding to a CCR6 chemokine receptor.
What genes are involved in CCR6 chemokine receptor binding?
Key genes include CCR6 (the receptor) and CCL20 (the ligand), as well as regulators like HuR and IL17D.
What is the ligand for CCR6?
The principal endogenous ligand for CCR6 is CCL20, also known as LARC or MIP-3alpha.
What diseases are associated with CCR6 chemokine receptor binding?
It is associated with chronic pancreatitis, colorectal cancer liver metastasis, skin inflammation, allergic asthma, and neuroinflammation.
How is CCR6 chemokine receptor binding studied?
It is studied using single-cell RNA-seq, flow cytometry, structural biology, extracellular vesicle analysis, and CRISPR models.
What is the role of CCR6 in Th17 cells?
CCR6 mediates Th17 cell recruitment to inflamed tissues, and its expression is promoted by the RNA-binding protein HuR.
Can CCR6 be targeted therapeutically?
Yes, the CCR6 antagonist PF-07054894 ameliorates IL-23-induced skin inflammation and increases circulating CCR6+ T cells.
What is the structural basis of CCL20-CCR6 binding?
Structural studies have resolved how CCL20 binds and activates CCR6, providing a basis for drug design.
How does CCR6-CCL20 crosstalk affect chronic pancreatitis?
Single-cell sequencing has revealed distinct immune microenvironments driven by CCR6-CCL20 crosstalk in human chronic pancreatitis.
What CRISPR models are available for CCR6 research?
Knockout, point mutation, knock-in, and overexpression models can be generated to study CCR6 function and binding.
Conclusion
GO:0031731 (CCR6 chemokine receptor binding) is a central molecular function that governs immune cell trafficking and tissue inflammation. The interaction between CCL20 and CCR6 is structurally defined and has been implicated in diverse pathologies, from chronic pancreatitis to cancer metastasis and allergic asthma. Pharmacological and genetic tools, including CRISPR models, continue to advance our understanding of this axis and its therapeutic potential. As research progresses, targeting CCR6 chemokine receptor binding may offer new opportunities for treating inflammatory diseases and cancer. EDITGENE provides the necessary CRISPR services to accelerate such discoveries.
References
- 1. Burger ML et al.. 2021. Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors.. Cell 184(19):4996-5014.e26 PMID: 34534464
- 2. Wasilko DJ et al.. 2020. Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.. Nat Commun 11(1):3031 PMID: 32541785
- 3. Talbot J et al.. 2020. Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier.. Nature 579(7800):575-580 PMID: 32050257
- 4. Lee B et al.. 2022. Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.. Gut 71(9):1831-1842 PMID: 34702715
- 5. Zhao S et al.. 2022. Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment.. J Extracell Vesicles 11(1):e12186 PMID: 35041299
- 6. Li W et al.. 2023. A Novel C-C Chemoattractant Cytokine (Chemokine) Receptor 6 (CCR6) Antagonist (PF-07054894) Distinguishes between Homologous Chemokine Receptors, Increases Basal Circulating CCR6(+) T Cells, and Ameliorates Interleukin-23-Induced Skin Inflammation.. J Pharmacol Exp Ther 386(1):80-92 PMID: 37142443
- 7. Yuan L et al.. 2025. Ciliated cell-derived IL-17D restrains allergic asthma through controlling monocyte recruitment.. J Exp Med 222(10) PMID: 40762706
- 8. Chen J et al.. 2017. The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells.. J Biol Chem 292(35):14532-14543 PMID: 28684423
