# CCL21
**CCL21** (C-C motif chemokine ligand 21), also known as secondary lymphoid-tissue chemokine (SLC), 6Ckine, thymus-derived chemotactic agent 4 (TCA4), or Exodus-2, is a human protein-coding chemokine that attracts T cells and dendritic cells and guides their traffic into lymphatic vessels and lymph nodes. It is a high-affinity functional ligand for the chemokine receptor CCR7, expressed on T and B lymphocytes, and its gene sits in the cluster of CC cytokine genes on the p-arm of chromosome 9.[1](https://www.ncbi.nlm.nih.gov/gene/6366)
| Key fact | Detail |
|---|---|
| Gene | CCL21, Gene ID 6366, HGNC:10620, protein coding, location 9p13.3, 4 exons[1](https://www.ncbi.nlm.nih.gov/gene/6366) |
| Protein | C-C motif chemokine 21, 124 amino acids, monomer, UniProt Q5VZ73[2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry) |
| Receptor | High-affinity functional ligand of CCR7; also binds the atypical receptor ACKR4[1](https://www.ncbi.nlm.nih.gov/gene/6366) • [2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry) |
| Cell targets | Chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils[1](https://www.ncbi.nlm.nih.gov/gene/6366) |
| Signature feature | A 37-amino-acid, highly positively charged C-terminal tail that binds glycosaminoglycans and immobilizes the chemokine on surfaces[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) |
| Expression | Biased expression in lymph node (RPKM 1020.3) and spleen (RPKM 170.8)[1](https://www.ncbi.nlm.nih.gov/gene/6366) |
| Main sources | High endothelial venules, lymphoid endothelial cells, and stromal cells in T cell areas of lymph nodes, spleen, and Peyer's patches[3](https://www.mdpi.com/2072-6694/6/2/1098) |
## Gene and protein
The CCL21 gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9, at band 9p13.3, and spans four exons.[1](https://www.ncbi.nlm.nih.gov/gene/6366) The encoded protein is 124 amino acids long and, like other CC chemokines, is characterized by two adjacent cysteines.[1](https://www.ncbi.nlm.nih.gov/gene/6366) • [2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry) It was formerly known as 6Ckine because it has six cysteine residues, in contrast to most other chemokines, which have four.[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) In solution it is a monomer.[2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry)
Like other chemokines, CCL21 inhibits hemopoiesis and stimulates chemotaxis.[1](https://www.ncbi.nlm.nih.gov/gene/6366) Its chemotactic activity in vitro is selective: it attracts thymocytes and activated T cells, and shows preferential activity toward naive T cells, but not B cells, macrophages, or neutrophils.[1](https://www.ncbi.nlm.nih.gov/gene/6366) • [2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry)
## The CCR7 axis and lymphocyte homing
CCL21 and CCL19 are the only two ligands of CCR7, a receptor expressed by B cells, mature dendritic cells, and several [T cell](https://www.edgepedia.org/t-cell) subpopulations including naive, regulatory, and central memory T cells.[5](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00568/full) • [10](https://www.nature.com/articles/nri2297) The chief role of the CCR7/CCL19/CCL21 axis is to create and maintain the anatomical settings in which antigen-presenting cells can engage in cognate encounters with antigen-specific lymphocytes, a process that lies at the heart of adaptive immunity.[11](https://www.sciencedirect.com/science/article/pii/S1359610113000191) Both chemokines are considered homeostatic: they are constitutively produced and, unlike most chemokines, are not normally induced by inflammation.[11](https://www.sciencedirect.com/science/article/pii/S1359610113000191)
The two ligands are expressed in different places. CCL21 is produced by [lymphatic capillary](https://www.edgepedia.org/lymphatic-capillary) endothelial cells in various tissues and in lymph nodes, whereas expression of CCL19 is restricted to lymph nodes.[8](https://aacrjournals.org/cancerres/article/80/17/3463/645836/Lymphatic-Vessels-in-Tumor-Dissemination-versus) Within lymphoid organs, CCR7 ligands are present on high endothelial venules and on stromal cells of the spleen, lymph node, and thymus.[10](https://www.nature.com/articles/nri2297) This arrangement underlies lymphocyte and dendritic cell homing to lymph nodes and intestinal Peyer's patches.[10](https://www.nature.com/articles/nri2297)
## Dendritic cell migration
A central role of CCL21 is guiding antigen-bearing dendritic cells from peripheral tissues into draining lymph nodes. CCR7 upregulation allows activated conventional dendritic cells to sense a haptotactic (movement guided along a surface-bound gradient) gradient of CCL21 generated by lymphatic endothelial cells, which attracts them into afferent lymphatics and subsequently into draining lymph nodes via the subcapsular sinus.[9](https://doi.org/10.1146/annurev-immunol-061020-053707) Through its engagement with CCR7, CCL21 allows dendritic cells to access lymphatic vessels and, ultimately, the lymph node that drains the tissue; once there, the cells move into the paracortex, a region rich in T cells, and display antigen to T cells.[14](https://www.nature.com/articles/nri.2016.116) In mice, arrival of antigen-bearing migratory dendritic cells at draining lymph nodes can occur as early as 8 to 12 hours after virus infection.[9](https://doi.org/10.1146/annurev-immunol-061020-053707)
## The C-terminal tail and glycosaminoglycan binding
The most prominent structural difference between CCL21 and CCL19 is CCL21's extended C-terminal region of about 40 residues (described as a 37-amino-acid tail in several studies), which is highly positively charged and required for immobilization of the chemokine on glycosaminoglycans (GAGs), the sugar chains on endothelial and extracellular-matrix surfaces.[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC5620614/) CCL19 lacks this domain and binds GAGs weakly.[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) This immobilization creates surface-bound gradients: full-length CCL21 induces integrin-dependent dendritic cell spreading, polarization, and haptotactic movement, whereas CCL21 missing the positively charged tail induces non-adhesive, integrin-independent directional migration.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7138053/)
GAG binding also modulates signaling. GAG-bound CCL21 obscures its interaction with CCR7, which can impair chemotaxis, and the tail interacts with polysialic acid at the N-terminus of CCR7, inducing ERK signaling via [G protein](https://www.edgepedia.org/g-protein).[6](https://portlandpress.com/biochemsoctrans/article/49/3/1385/228848/Latest-update-on-chemokine-receptors-as?searchresult=1) In the presence of cooperative chemokines, CCL19 and CCL21 are competed away from GAGs, increasing the concentration of chemokine available to interact with the receptor.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7138053/)
## Biased signaling compared with CCL19
CCL19 and CCL21 share only 32% amino acid identity yet bind the same receptor, and they are a standard example of ligand bias at a chemokine receptor.[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) Both ligands activate G protein signaling with similar efficacy, but only CCL19 induces receptor phosphorylation, β-arrestin recruitment, and clathrin-mediated internalization of CCR7; CCL21 does not efficiently internalize the receptor.[4](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full) • [5](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00568/full) In general, CCL19 generates a strong, short-lived signal, whereas CCL21 generates a weaker but more persistent one.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8348795/)
The tail shapes these differences. CCL21 induces prolonged and more efficient ERK1/2 activation than CCL19 in dendritic cells, and removal of sialic acid from the cell surface impairs ERK1/2 activation by CCL21 but not by CCL19 or tailless-CCL21.[5](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00568/full) Yet the tail does not improve receptor docking: both CCL21 and tailless-CCL21 show low potency in G protein activation and β-arrestin recruitment compared with CCL19, and CCL19 is 10 to 100 times more potent than CCL21 in inducing directed migration of dendritic cells.[5](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00568/full) • [13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8348795/) Later work showed that the biased signaling of the two ligands does not rely on their N-terminal differences but markedly on the chemokine core domains and extracellular loop 2 of CCR7.[7](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02156/full)
Dendritic cells themselves can reshape the ligand. Proteases released by dendritic cells cleave full-length CCL21, removing its heparin sulfate-binding domain and generating a soluble tailless-CCL21 that induces chemotaxis but not adhesion and acts more like CCL19.[7](https://jlb.onlinelibrary.wiley.com/doi/10.1189/jlb.2MR0815-380R) • [13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8348795/) CCL21 is also internalized via the atypical chemokine receptor ACKR4, which does not mediate cell migration, making the cleaved signal short-lived like CCL19.[2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry) • [13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8348795/)
## Roles in cancer and inflammation
Because the CCL19/CCL21/CCR7 axis organizes antigen presentation and T cell activation, raising CCL21 levels within tumors has been proposed as a way to enhance antitumor immune responses.[16](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.147) In preclinical work, dendritic cells transduced with adenoviral CCL21 produced up to 210 ± 9 ng/mL (multiplicity of infection 50:1) and 278 ± 6.5 ng/mL (MOI 100:1) of human CCL21 per 106 cells per 48 hours in vitro, and intratumoral injection of such CCL21-expressing dendritic cells was proposed to capture tumor antigens, present them to recruited lymphocytes, and launch an enhanced immune response.[17](https://www.mdpi.com/2072-6694/6/2/1098/pdf?version=1399534349)
The axis cuts both ways in tumors. Tumor cells can occasionally acquire CCR7 expression, promoting their directed migration toward lymphatic vessels and invasion of lymph node parenchyma; CCR7 expression by tumor cells correlates with lymph node metastasis of gastric carcinoma, colorectal carcinoma, and breast cancer.[8](https://aacrjournals.org/cancerres/article/80/17/3463/645836/Lymphatic-Vessels-in-Tumor-Dissemination-versus) [VEGFC](https://www.edgepedia.org/vegfc) produced by tumor cells increases CCL21 expression in nearby lymphatic endothelium, a paracrine cross-talk that can foster lymph node metastasis.[8](https://aacrjournals.org/cancerres/article/80/17/3463/645836/Lymphatic-Vessels-in-Tumor-Dissemination-versus) Conversely, the atypical receptor ACKR4 restrains antitumor immunity by decreasing intratumor CCL21: deleting ACKR4 in mice increased intratumor CCL21, retained CD103+ dendritic cells and CD8+ T lymphocytes, and inhibited tumor growth.[8](https://aacrjournals.org/cancerres/article/80/17/3463/645836/Lymphatic-Vessels-in-Tumor-Dissemination-versus)
In inflammatory disease, genome-wide association studies have identified CCL21 as a risk factor for rheumatoid arthritis, and CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in that disease.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC10040247/pdf/18_2019_Article_3235.pdf) While CCL19 and CCL21 can both increase T cell chemotaxis, only CCL21 promotes extravasation.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC10040247/pdf/18_2019_Article_3235.pdf)
## Additional interactions
Beyond CCR7, CCL21 binds ACKR4 and mediates recruitment of β-arrestin (ARRB1/2) to ACKR4, and it interacts with podoplanin (PDPN), relocalizing PDPN to the basolateral membrane, with [TNFAIP6](https://www.edgepedia.org/tnfaip6) via its Link domain, and with GPR174.[2](https://www.uniprot.org/uniprotkb/Q5VZ73/entry) CCL21 also binds mast cells and the extracellular matrix in rheumatoid arthritis synovium, binding that is inhibited by high salt concentrations and GAGs.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7138053/)
## References
1. [CCL21 C-C motif chemokine ligand 21 [Homo sapiens (human)], NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/6366)
2. [C-C motif chemokine 21 (Q5VZ73), UniProtKB](https://www.uniprot.org/uniprotkb/Q5VZ73/entry)
3. [CCL21 Cancer Immunotherapy, Cancers (MDPI)](https://www.mdpi.com/2072-6694/6/2/1098)
4. [Biased and G Protein-Independent Signaling of Chemokine Receptors, Frontiers in Immunology (2014)](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00277/full)
5. [Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC-Chemokines, Frontiers in Immunology (2016)](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00568/full)
6. [Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation, Frontiers in Immunology (2020)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7138053/)
7. [Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes, Journal of Leukocyte Biology (2016)](https://jlb.onlinelibrary.wiley.com/doi/10.1189/jlb.2MR0815-380R)
8. [Lymphatic Vessels in Tumor Dissemination versus Immunotherapy, Cancer Research (2020)](https://aacrjournals.org/cancerres/article/80/17/3463/645836/Lymphatic-Vessels-in-Tumor-Dissemination-versus)
9. [Dendritic Cells Revisited, Annual Review of Immunology (2021)](https://doi.org/10.1146/annurev-immunol-061020-053707)
10. [Förster R, Davalos-Misslitz AC, Rot A (2008). CCR7 and its ligands: balancing immunity and tolerance. Nature Reviews Immunology 8, 362–371](https://www.nature.com/articles/nri2297)
11. [A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system, Immunological Reviews](https://www.sciencedirect.com/science/article/pii/S1359610113000191)
12. [CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis](https://pmc.ncbi.nlm.nih.gov/articles/PMC10040247/pdf/18_2019_Article_3235.pdf)
13. [Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer](https://pmc.ncbi.nlm.nih.gov/articles/PMC8348795/)
14. [Dendritic cell migration in health and disease, Nature Reviews Immunology (2017)](https://www.nature.com/articles/nri.2016.116)
15. [Latest update on chemokine receptors as therapeutic targets, Biochemical Society Transactions (2021)](https://portlandpress.com/biochemsoctrans/article/49/3/1385/228848/Latest-update-on-chemokine-receptors-as?searchresult=1)
16. [Role of chemokine systems in cancer and inflammatory diseases, MedComm](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.147)
17. [CCL21 Cancer Immunotherapy (PDF version), Cancers (MDPI)](https://www.mdpi.com/2072-6694/6/2/1098/pdf?version=1399534349)
18. [Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System, International Journal of Molecular Sciences (2017)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5620614/)
19. [Biased Signaling of CCL21 and CCL19 Does Not Rely on N-Terminal Differences, but Markedly on the Chemokine Core Domains and Extracellular Loop 2 of CCR7, Frontiers in Immunology (2019)](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02156/full)
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*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records › Cytokine and immune-response genes › Chemokines and chemokine receptors*
*Initially written Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license