Affinage

CCL21

C-C motif chemokine 21 · UniProt O00585

Length
134 aa
Mass
14.6 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL21 is a constitutively expressed CC chemokine that serves as the principal ligand for CCR7 in organizing immune cell trafficking, lymphoid tissue architecture, and neuroimmune communication. Through CCR7, CCL21 activates LFA-1 on rolling T cells to trigger firm adhesion at high endothelial venules, costimulates CD4+ T cell activation via DOCK2/Rac-ERK signaling, promotes dendritic cell migration from peripheral tissues to draining lymph nodes, and drives activation-induced cell death during clonal contraction (PMID:10620605, PMID:19451552, PMID:20201039, PMID:16973962). CCL21 also signals through CXCR3 to exert angiostatic effects and through GPR174 to regulate sex-biased B cell migration, while its unique C-terminal extension mediates heparan sulfate-dependent immobilization on stromal cells to form functional chemokine gradients shaped by ACKR4-mediated scavenging (PMID:9653165, PMID:31875850, PMID:29768676, PMID:33875601, PMID:33570638). In the nervous system, neuronal CCL21 is sorted into large dense-core vesicles, transported axonally to the spinal dorsal horn, and upregulates microglial P2X4 receptors to initiate neuropathic pain after nerve injury (PMID:18697841, PMID:21441897).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Establishing that CCL21 signals through a second receptor (CXCR3) in addition to its primary receptor CCR7 expanded its functional repertoire to include angiostatic activity shared with CXC chemokines.

    Evidence Calcium flux assay in CXCR3-transfected cells plus Matrigel angiostasis assay

    PMID:9653165

    Open questions at the time
    • Whether CXCR3-mediated angiostasis is relevant in vivo in tumor microenvironments was not resolved
    • Relative contribution of CXCR3 vs. CCR7 signaling in different cell types unclear
  2. 1999 High

    Identification of two distinct CCL21 genes in mice, with one deleted in plt/plt mice, provided the genetic basis for the T cell homing defect and established plt/plt as a bona fide CCL21-deficiency model.

    Evidence Genomic deletion mapping in plt/plt mice

    PMID:10523616

    Open questions at the time
    • Functional difference between the two mouse CCL21 gene products not fully defined
    • Whether human CCL21 gene regulation parallels the two-gene system was unresolved
  3. 2000 High

    CCL21 was shown to be the critical chemokine presented on HEV luminal surfaces that triggers LFA-1-mediated T cell arrest via CCR7/Gαi signaling, and its ectopic expression sufficed to drive lymphoid neogenesis with organized HEVs and stromal reticulum.

    Evidence Intravital microscopy with CCR7 desensitization and plt/plt reconstitution; transgenic islet-specific CCL21 expression in RAG-1 and Ikaros KO backgrounds; tumor transduction with CCL21 cDNA plus antibody depletion experiments

    PMID:10620605 PMID:10754285 PMID:10925282

    Open questions at the time
    • Mechanism by which CCL21 induces HEV differentiation and stromal remodeling not defined
    • Relative roles of CCL21 vs. CCL19 in lymphoid neogenesis unresolved
  4. 2002 Medium

    Demonstrating that glycosaminoglycans regulate CCL21 bioavailability by modulating its local concentration established the importance of GAG interactions for CCL21 gradient function.

    Evidence T cell adhesion and chemotaxis assays with heparinase treatment and low-molecular-weight heparins

    PMID:12065729

    Open questions at the time
    • Specific GAG structures involved not identified
    • In vivo relevance of GAG-mediated CCL21 regulation not demonstrated at this stage
  5. 2004 High

    CCL21 was shown to participate in fetal thymus colonization by T cell precursors, extending its role from peripheral lymphoid homing to thymic seeding.

    Evidence Time-lapse fetal thymus colonization assay with anti-CCL21 neutralization and plt/plt mice

    PMID:15358618

    Open questions at the time
    • Relative contribution of CCL21 vs. CCL25 in thymic colonization not fully dissected
    • Whether CCL21 acts as a chemoattractant or a retention signal for thymic progenitors was unclear
  6. 2006 High

    Two new functional dimensions of CCL21 were established: promotion of renal fibrosis via CCR7+ fibrocyte recruitment, and regulation of T cell clonal contraction through enhancement of Fas ligand-mediated AICD.

    Evidence Ureteral obstruction model with anti-CCL21 antibody and CCR7-null mice; plt/plt mice immunized with OVA/CFA with in vitro AICD assays

    PMID:16966615 PMID:16973962

    Open questions at the time
    • Whether CCL21 directly upregulates FasL on T cells or acts indirectly through DCs not resolved
    • Contribution of CCL21 vs. CCL19 to AICD not fully separated
  7. 2008 High

    Discovery that neuronal CCL21 is sorted into large dense-core vesicles and preferentially transported into axons established a mechanism for directed neuron-to-microglia signaling distinct from its immunological roles.

    Evidence Live-cell imaging of CCL21-vesicle trafficking with subcellular fractionation in primary neurons

    PMID:18697841

    Open questions at the time
    • The receptor on microglia mediating CCL21 responses in the CNS was not identified at this point
    • Stimulus for neuronal CCL21 transcriptional induction after injury was unknown
  8. 2009 High

    The intracellular signaling cascade downstream of CCR7/CCL21 in T cells was mapped: DOCK2/Rac activation feeds into ERK/MEK phosphorylation to costimulate TCR signaling, while PLCγ1 and ERK1/2 form a positive feedback loop required for T cell migration on fibronectin.

    Evidence DOCK2-deficient, PI3Kδ kinase-dead, and PI3Kγ-deficient primary T cells with GTPase activation assays; PLCγ1 shRNA knockdown with MEK inhibitor treatment in migration assays

    PMID:19451552 PMID:20889506

    Open questions at the time
    • How DOCK2 is recruited to the CCR7 signaling complex was not defined
    • Whether the PLCγ1-ERK feedback loop operates in all CCR7-expressing cell types was untested
  9. 2010 High

    CCL21 alone was shown to be sufficient for DC migration from skin, DC maturation, and T cell priming, establishing CCL19 as functionally redundant for these processes.

    Evidence CCL19-deficient mice with varying CCL21 expression levels; DC frequency and T cell priming assays

    PMID:20201039

    Open questions at the time
    • Whether CCL19 has non-redundant roles in other contexts (e.g., T cell zone positioning) remained open
    • Dose-response relationship for CCL21 in sustaining immune homeostasis not defined
  10. 2011 High

    The neuronal CCL21 pathway was completed: CCL21 transported to dorsal horn central terminals upregulates microglial P2X4 receptors to initiate neuropathic pain, as CCL21 knockout prevents allodynia and intrathecal CCL21 rescues it in a P2X4-dependent manner.

    Evidence CCL21 knockout mice with nerve injury; intrathecal CCL21 injection rescue; P2X4 expression assays on microglia

    PMID:21441897

    Open questions at the time
    • The microglial receptor for CCL21 in the CNS that triggers P2X4 upregulation was not identified (neither CCR7 nor CXCR3 was confirmed)
    • Whether CCL21 acts directly on microglia or through an intermediate cell type was not definitively established
  11. 2013 High

    CCL21 was shown to be specifically required for nerve injury-evoked but not autoimmune-evoked neuropathic pain, while CXCR3 mediates the latter, demonstrating context-dependent dichotomy among CCL21's receptor pathways in pain.

    Evidence plt/plt mice, CXCR3-/- mice, and double knockouts tested in sciatic nerve injury vs. EAE models with behavioral pain testing

    PMID:23643685

    Open questions at the time
    • Mechanism distinguishing traumatic vs. autoimmune pain pathways downstream of CCL21 undefined
    • Whether CXCR3 contributes to CCL21-mediated nerve injury pain was not excluded
  12. 2017 High

    Structural NMR revealed that CCR7 sulfotyrosine modifications at Y8 and Y17 enhance CCL21 binding by engaging distinct epitopes near the α-helix and N-loop/β3-strand, providing the first atomic-level view of the CCL21-CCR7 interaction.

    Evidence Protein NMR with CCR7 N-terminal peptides containing Tyr, phosphoTyr, or sulfoTyr modifications

    PMID:28841151

    Open questions at the time
    • Full-length CCR7 structure in complex with CCL21 not available
    • Functional consequences of sulfotyrosine modifications on CCR7 signaling in cells not tested
  13. 2018 High

    Domain-swap mutagenesis established that CCL21's C-terminal extension autoinhibits CCR7 cAMP signaling while enhancing GAG binding, explaining how immobilized CCL21 creates haptotactic gradients with attenuated receptor activation; separately, CCL21-Ser was shown to specifically guide cDC1 progenitor migration to the thymus.

    Evidence CCL21/CCL19 chimeric proteins with calcium, cAMP, chemotaxis, and receptor internalization assays; CCR7-/-, CCL21Ser-/-, CCL19-/- mice with thymic DC subset analysis

    PMID:29768676 PMID:29784760

    Open questions at the time
    • Structural basis for C-terminal tail autoinhibition not resolved
    • Whether proteolytic removal of the tail is regulated in specific physiological contexts was not tested
  14. 2019 High

    GPR174 was identified as a third receptor for CCL21, mediating sex-biased B cell migration through testosterone-regulated Gαi coupling, revealing an unexpected layer of CCL21 signaling beyond CCR7 and CXCR3.

    Evidence Biochemical fractionation identifying CCL21 as GPR174 ligand; calcium flux; B cell migration; GPR174 conditional deletion; orchidectomy and testosterone treatment

    PMID:31875850

    Open questions at the time
    • Physiological relevance of GPR174/CCL21 axis in lymphoid organ homeostasis not fully characterized
    • Whether GPR174 and CCR7 compete for CCL21 or transduce distinct signals on the same cell was unexplored
  15. 2020 High

    Two studies established CCL21 as a functionally bidirectional signal in tumors: ACKR4 scavenging on non-hematopoietic cells limits intratumoral CCL21, restricting CD103+ DC retention and anti-tumor immunity, while CCL21/CCR7 on pancreatic cancer cells promotes perineural invasion and pain.

    Evidence ACKR4-deficient mice with bone marrow chimeras and tumor-infiltrating leukocyte analysis; RNAi screen with orthotopic PDAC model and CCL21/CCR7 neutralization

    PMID:32289156 PMID:32330476

    Open questions at the time
    • Whether therapeutic CCL21 augmentation in tumors would enhance immunotherapy efficacy was not tested
    • Mechanism by which CCL21 promotes nerve fiber hypertrophy in PDAC unknown
  16. 2021 High

    The CCL21 gradient-shaping mechanism was defined: ACKR4 scavenges both immobilized and cleaved soluble CCL21 forms, while heparan sulfate on pericytes and adventitial cells captures full-length CCL21 via its C-terminal extension, creating functional gradients for DC and thymocyte migration.

    Evidence ACKR4-deficient mice with quantification of two CCL21 forms; CCL21/CCL19-deficient mice with cell-type fractionation and heparan sulfate dependency assays in thymus

    PMID:33570638 PMID:33875601

    Open questions at the time
    • Whether specific heparan sulfate sulfation patterns determine CCL21 capture efficiency is unknown
    • Dynamics of CCL21 cleavage (protease identity, regulation) not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The microglial receptor through which CCL21 upregulates P2X4 in the CNS remains unidentified, the structural basis of the CCL21 C-terminal tail autoinhibition is unresolved, and the functional interplay among CCR7, CXCR3, and GPR174 on cells co-expressing these receptors has not been dissected.
  • CNS receptor for CCL21 on microglia not identified
  • No full-length CCR7-CCL21 co-structure available
  • Signaling crosstalk between CCR7, CXCR3, and GPR174 on co-expressing cells uncharacterized
  • Protease responsible for C-terminal tail cleavage generating soluble CCL21 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0008289 lipid binding 3
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3
Partners
ACKR4CCR7CXCR3DOCK2GPR174LFA-1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CCL21 (TCA-4/SLC/6Ckine) is constitutively presented on the luminal surface of high endothelial venules (HEVs) in peripheral lymph nodes, where it activates LFA-1 on rolling T cells via CCR7 (a Gαi-linked receptor), triggering firm adhesion; CCL21 delivered via afferent lymph to draining PLNs was sufficient to restore LFA-1-mediated T cell arrest in plt/plt HEVs that lack endogenous CCL21. Intravital microscopy of murine PLNs with adoptively transferred GFP+ T cells; CCR7 desensitization; intracutaneous injection of CCL21 into plt/plt mice The Journal of experimental medicine High 10620605
1998 The CC chemokine 6Ckine (CCL21) binds and activates the CXC chemokine receptor CXCR3 in addition to CCR7, inducing calcium flux in CXCR3-transfected cells; CCL21 also displays angiostatic properties similar to other CXCR3 ligands. Calcium flux assay in mouse CXCR3-transfected cells screened against a panel of chemokines; Matrigel angiostasis assay Proceedings of the National Academy of Sciences of the United States of America High 9653165
1999 Mouse 6Ckine (CCL21) is encoded by two distinct genes; one gene expressed in lymphoid organs is deleted in plt/plt mice, explaining the absence of CCL21 in lymphoid tissues of those mice and their T cell homing defect. Genomic analysis, gene deletion mapping in plt/plt mice The Journal of experimental medicine High 10523616
2000 Ectopic expression of CCL21 (TCA4/SLC) in pancreatic islets is sufficient to trigger lymphoid neogenesis, recruiting naive T cells and dendritic cells (which express CCR7) and inducing organized lymphoid tissue with high endothelial venules and stromal reticulum; B cell recruitment required T cells/DCs as intermediaries. Transgenic mouse model with islet-specific CCL21 expression; backcross to RAG-1 and Ikaros knockout mice Journal of immunology High 10754285
2000 Mouse CCL21/SLC exerts antitumor effects through two mechanisms: (1) angiostasis via interaction with CXCR3, and (2) induction of CD8+ T cell- and NK cell-mediated tumor-specific immunity; tumor-infiltrating DCs retained an immature phenotype. Tumor cell transduction with CCL21 cDNA; in vivo Matrigel assay for angiostasis; antibody depletion of CD8+ T cells and NK cells; immunohistochemistry Journal of immunology High 10925282
2004 CCL21 is involved in recruitment of T-cell precursors to the fetal thymus; neutralizing antibodies against CCL21 (and CCL25) markedly diminish fetal thymus colonization, and CCL21-deficient plt/plt mice show partial defects in this colonization. Time-lapse visualization culture of fetal thymus colonization; neutralizing antibody blockade; plt/plt mice Blood High 15358618
2008 Neuronal CCL21 is sorted into large dense-core vesicles (the regulated secretory pathway) and preferentially transported into axons, establishing a mechanism for directed neuron-to-microglia communication from injured neurons. Live-cell imaging of CCL21-vesicle trafficking; subcellular fractionation; fluorescence microscopy of axonal vs. dendritic sorting FASEB journal High 18697841
2011 CCL21 expressed in injured primary sensory neurons is transported to central terminals in the dorsal horn, where it up-regulates microglial P2X4 receptor expression to initiate neuropathic pain (tactile allodynia); CCL21-deficient mice do not develop allodynia or upregulate P2X4, and intrathecal CCL21 restores allodynia in CCL21-deficient nerve-injured mice in a P2X4-dependent manner. CCL21 knockout mice, intrathecal antibody blockade, intrathecal CCL21 injection, in vitro CCL21 application to microglia, P2X4 receptor expression assays The EMBO journal High 21441897
2009 CCL21 costimulates CD4+ T cell activation via CCR7 through a DOCK2/Rac-dependent pathway: CCL21 during early TCR signaling increases Ras- and Rac-GTP formation, phosphorylation of Akt, MEK, and ERK (but not p38 or JNK), lowering the T cell activation threshold; DOCK2 deficiency impairs CCL21 costimulation and Rac-GTP formation. Primary TCR-transgenic CD4+ T cells; kinase-dead PI3Kδ and PI3Kγ-deficient mice; DOCK2-deficient mice; GTPase activation assays; lymph node slice live imaging Blood High 19451552
2010 CCR7/CCL21-mediated T lymphocyte migration on fibronectin requires rapid, transient ERK1/2 phosphorylation (within 2 min) downstream of PLCγ1; PLCγ1 shRNA knockdown reduces ERK1/2 phosphorylation and CCR7-mediated migration, and ERK1/2 inhibition reduces PLCγ1 phosphorylation, indicating a feedback loop between ERK1/2 and PLCγ1. shRNA knockdown of PLCγ1; pharmacological inhibition of MEK (U0126) and PLC (U73122); phosphorylation assays; migration assays on fibronectin The Journal of biological chemistry High 20889506
2010 CCL21 alone (without CCL19) is sufficient to mediate DC migration from skin, DC maturation, and efficient T cell priming in vivo; CCL19 is redundant for these processes, as demonstrated in CCL19-deficient mice expressing various levels of CCL21. CCL19-deficient mice with varying CCL21 expression levels; flow cytometry of DC frequencies and localization; T cell priming assays European journal of immunology High 20201039
2019 GPR174, an X-chromosome-encoded GPCR, is identified as a receptor for CCL21; CCL21 triggers GPR174-mediated calcium flux and preferentially induces migration of male B cells; GPR174 associates more strongly with Gαi protein in male than female B cells, and this sex difference is regulated by testosterone. Biochemical fractionation of conditioned media; calcium flux assay; B cell migration assay; Co-IP of GPR174-Gαi; orchidectomy and testosterone treatment; GPR174 conditional deletion Nature High 31875850
2021 ACKR4 scavenges two forms of CCL21 in barrier tissues — full-length immobilized and cleaved soluble CCL21 — to establish functional extracellular CCL21 gradients; without ACKR4, CCL21 gradients are saturated and non-functional, DCs cannot home to lymphatic vessels, and excess soluble CCL21 from peripheral tissues floods downstream lymph nodes. ACKR4-deficient mice; quantification of CCL21 forms in skin and LNs; DC migration assays; flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 33875601
2002 Low-molecular-weight heparins (and glycosaminoglycans) strongly inhibit CCL21-induced T cell adhesion and chemotaxis; enzymatic cleavage of GAGs abrogates this inhibition, revealing that heparin-like GAGs regulate CCL21 function by modulating its local availability. T cell adhesion and chemotaxis assays with heparinase treatment and low-molecular-weight heparins The Journal of pharmacology and experimental therapeutics Medium 12065729
2002 CCL21 expression is induced in endothelial cells during T cell autoimmune skin diseases, where its receptor CCR7 is expressed on infiltrating memory T cells (CD45Ro+), suggesting a role for CCL21/CCR7 in mediating T cell infiltration at sites of autoimmune inflammation. Immunohistology of T-cell autoimmune skin disease specimens Blood Low 12393410
2003 CCL21 activates CCR7 on hepatic stellate cells (HSCs), triggering ERK, Akt, and NF-κB signaling pathways, stimulating HSC migration and wound healing in vitro, and inducing pro-inflammatory gene expression, implicating CCL21/CCR7 in hepatic fibrogenesis. In vitro HSC migration assay; wound healing assay; Western blot for ERK, Akt, NF-κB; CCR7 expression by flow cytometry Gastroenterology Medium 14517790
2004 CCL21 (SLC/CCL21) binding to CCR7 on human mesangial cells enhances their adhesion to fibronectin in a time- and concentration-dependent manner, activates integrin-linked kinase (ILK) leading to phosphorylation of GSK-3 and PKB/Akt, and causes F-actin rearrangements with membrane ruffling. Adhesion assays; mechanical detachment assays; ILK activity assay; phalloidin immunofluorescence for F-actin Kidney international Medium 15569314
2006 CCL21/CCR7 signaling promotes the migration of CCR7+ fibrocytes into the kidney in response to CCL21+ vessels during renal fibrosis; blockade of CCL21/CCR7 (anti-CCL21 antibodies or CCR7-null mice) reduced fibrocyte infiltration, renal fibrosis, TGF-β1 and collagen I transcripts, and macrophage recruitment. Unilateral ureteral obstruction mouse model; anti-CCL21 antibody blockade; CCR7-null mice; immunohistochemistry; qRT-PCR Proceedings of the National Academy of Sciences of the United States of America High 16966615
2009 CCR7-CCL19/CCL21 pathway is required for antigen-bearing dendritic cells to migrate from sublingual mucosa to cervical lymph nodes and prime antigen-specific T and B cell responses; depletion of CD11c+ cells or CCR7 deficiency abolished T cell proliferation after sublingual vaccination. CCR7-/- mice; CD11c depletion; reconstitution with OVA-specific CD4+/CD8+ T cells; flow cytometry; antibody measurement Journal of immunology High 19454681
2012 CCL21 (but not CCL19) induces human microvascular endothelial cell (HMVEC) migration and tube formation via CCR7 through the PI3K pathway; CCL21 promotes blood vessel growth in Matrigel plugs in vivo at concentrations found in RA joints, identifying CCL21 as a direct mediator of angiogenesis. HMVEC chemotaxis assays; tube formation assays; PI3K/ERK/JNK pathway inhibitors; in vivo Matrigel plug assay; CCR7 neutralization Arthritis and rheumatism High 22392503
2012 CCL21/CCR7 activation prevents apoptosis in non-small cell lung cancer cells by upregulating Bcl-2 and downregulating Bax and caspase-3 via the ERK pathway; co-immunoprecipitation confirmed interaction between p-ERK and Bcl-2/Bax/caspase-3. Flow cytometry apoptosis assay; Western blot and qRT-PCR; MEK inhibitor PD98059; CCR7 siRNA knockdown; co-immunoprecipitation PloS one Medium 22438908
2015 CCL21/CCR7 axis promotes breast cancer-associated lymphangiogenesis by upregulating VEGF-C secretion via AKT signaling; in vivo, CCR7/CCL21-expressing breast cancer cells promote lymph-vascular recruitment; in vitro, CCL21/CCR7 drives LEC proliferation, migration, and tube formation. In vivo orthotopic nude mouse model with CCR7/CCL21 gene-manipulated cells; in vitro LEC functional assays; Western blot for AKT; qRT-PCR; IHC Molecular cancer Medium 25744065
2018 Formation of intrathymic dendritic cell type 1 (cDC1) pool requires CCR7-CCL21Ser interactions to guide migration of CCR7+ cDC progenitors to the thymus; mice lacking CCR7 or CCL21Ser (but not CCL19) show selective reduction in thymic cDC1. CCR7-/-, CCL21Ser-/-, and CCL19-/- mice; flow cytometry of thymic DC subsets; progenitor identification Journal of immunology High 29784760
2021 CCL21 neonatal thymus emigration is mediated by CCL21 (not CCL19); CCL21 gene expression occurs in medullary epithelial subsets while CCL21 protein is captured and presented at sites of thymic exit by integrin α7+ pericytes and CD34+ adventitial cells via heparan sulfate-dependent interaction with CCL21's C-terminal extension; CCL19 (which lacks this domain) is not captured by thymic stroma. CCL21- and CCL19-deficient mice; Ccl21 gene expression mapping; CCL21 protein distribution analysis; cell-type fractionation; heparan sulfate dependency assays Blood advances High 33570638
2017 CCR7 sulfotyrosine (sY) at positions Y8 and Y17 enhances CCL21 binding affinity; sY8-containing peptides bind near the CCL21 α-helix while sY17-containing peptides bind near the N-loop and β3-strand; phosphotyrosine also enhances binding but less than sulfotyrosine. Protein NMR spectroscopy of CCL21 with CCR7 N-terminal peptides containing Tyr, phosphoTyr, or sulfoTyr International journal of molecular sciences High 28841151
2018 Fluorescently tagged CCL21-mRFP retains functional activity and can be used to visualize and quantify CCL21 gradients in real time; CCL21-mRFP is internalized by CCR7-expressing cells and scavenged by ACKR4, enabling spatiotemporal study of receptor trafficking and chemokine gradient formation. Fusion protein production; receptor trafficking assays; chemokine scavenging assays; live-cell gradient visualization International journal of molecular sciences Medium 30518137
2018 CCL21's C-terminal extension mediates its enhanced binding to glycosaminoglycans (GAGs) on dendritic cell surfaces; transfer of CCL21-tail to CCL19 increases GAG binding but negatively affects cAMP signaling potency; removal of CCL21 tail (CCL21tailless) increases cAMP signaling compared to full-length CCL21, indicating the C-terminal tail autoinhibits CCR7 signaling. CCL21/CCL19 chimeric proteins; calcium release assays; cAMP assays in CHO cells; DC chemotaxis assays; CCR7 internalization assays Journal of leukocyte biology High 29768676
2020 CCL21 promotes migration of pancreatic cancer cells toward sensory neurons via CCR7 expressed on cancer cells; neutralization of CCL21 or CCR7 in mice with orthotopic tumors reduces nociceptive hypersensitivity and nerve fiber hypertrophy without affecting tumor immune infiltration. RNA interference screen; PDAC cell migration assays; neutralizing antibody treatment in orthotopic tumor model; abdominal mechanical hypersensitivity testing; histology Gastroenterology High 32330476
2020 CCL21/CCR7 interaction activates JAK2/STAT3 signaling in oral squamous cell carcinoma cells, promoting EMT and cancer stem cell properties (CD133, CD44, BMI1, ALDH1A1, OCT4 upregulation); JAK2/STAT3 inhibition suppresses these CCL21-induced effects. Exogenous CCL21 stimulation; CCR7 knockdown and overexpression; JAK2/STAT3 inhibitor treatment; Western blot; migration/invasion/tumorsphere assays Journal of cellular physiology Medium 32017846
2009 CCL21 induces calcium transients in primary mouse astrocytes via CXCR3 at low concentrations; at high CCL21 concentrations (10⁻⁷ M), calcium transients persist in CXCR3-deficient astrocytes, and CCL21-induced proliferation is not impaired in CXCR3-deficient astrocytes, indicating CCL21 activates an additional, as-yet unidentified receptor on astrocytes. Calcium imaging; CXCR3-deficient astrocytes; CXCL10 comparison; proliferation assays Brain, behavior, and immunity Medium 19401230
2006 CCL21/CCL19 produced in secondary lymphoid organs promote activation-induced cell death (AICD) of antigen-responding CD4+ T cells during the clonal contraction phase, partly by enhancing Fas ligand expression; plt/plt mice lacking CCL21/CCL19 show prolonged CD4+ T cell responses without increased apoptosis. plt/plt mice immunized with OVA/CFA; in vivo tracking of OVA-responding CD4+ T cells; in vitro AICD assay with CCL19/CCL21; Fas ligand expression analysis Blood High 16973962
2011 ZAP-70 expression in CLL B cells enhances CCR7 upregulation after IgM stimulation via the ERK1/2 (MAPK) pathway, increasing CCR7 signaling and migration toward CCL21; ERK1/2 inhibition impairs CCR7 upregulation and CCL21-directed migration. ZAP-70-transfected Ramos cell line; ERK1/2, Akt, Syk phosphorylation assays; CCR7 expression by flow cytometry; migration assay toward CCL21; primary CLL samples Blood Medium 21865343
2015 CCL21-CCR7 promotes lymph node metastasis of esophageal squamous cell carcinoma by upregulating MUC1 via ERK1/2-mediated phosphorylation of Sp1, which increases Sp1 binding to the MUC1 promoter at -99/-90; Akt is also activated but is not responsible for MUC1 transcriptional upregulation. Transwell migration/invasion assays; luciferase reporter assay; Western blot for ERK, Akt, Sp1; ChIP for Sp1 binding to MUC1 promoter; MUC1 knockdown Journal of experimental & clinical cancer research Medium 26667143
2015 CCL21 facilitates chemoresistance and cancer stem cell properties in colorectal cancer via the AKT/GSK-3β/Snail signaling pathway, upregulating P-glycoprotein and stem cell markers (Bmi-1, Nanog, OCT-4) at the post-transcriptional level; PI3K/Akt inhibitor (LY294002) abolishes these effects. CCL21 treatment of HCT116 cells; Western blot; PI3K inhibitor LY294002; mammosphere formation assay; cell survival assay Oxidative medicine and cellular longevity Medium 27057280
2013 CCL21 (via CCR7/CCL21 axis, assessed in plt/plt mice) is required for nerve injury-evoked tactile allodynia but not autoimmunity-evoked (EAE) hyperalgesia; conversely, CXCR3 mediates EAE-evoked hyperalgesia but not traumatic nerve injury pain, demonstrating dichotomous roles for CCL21 ligands in different neuropathic pain contexts. plt/plt mice; CXCR3-/- mice; double knockout mice; sciatic nerve injury; EAE model; behavioral pain testing; spinal cord immunophenotyping Brain, behavior, and immunity High 23643685
2020 ACKR4 on non-hematopoietic cells controls intratumoral CCL21 abundance, which in turn regulates CD103+ dendritic cell retention in tumors and CD8+ T cell accumulation; in the absence of ACKR4, increased intratumoral CCL21 promotes anti-tumor immunity and inhibits tumor growth. ACKR4-deficient mice; bone marrow chimeras to define non-hematopoietic ACKR4 requirement; flow cytometry of tumor-infiltrating leukocytes; CCL21 quantification in tumors The Journal of experimental medicine High 32289156
2023 In severe COVID-19, CCL21 overexpression in activated adventitial niches is associated with endothelial-to-mesenchymal transition and tissue fibrosis, and links to accumulation of CCR7-expressing exhausted T cells that form lymphoid aggregates and ectopic lymphoid structures. Advanced imaging; spatial transcriptomics of COVID-19 lung tissue; immunophenotyping Nature communications Medium 36774347

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 The ABCs of membrane transporters in health and disease (SLC series): introduction. Molecular aspects of medicine 452 23506860
1999 Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 418 10421367
2000 The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. The Journal of experimental medicine 304 10620605
2018 Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 295 30464343
2009 Analysis and update of the human solute carrier (SLC) gene superfamily. Human genomics 250 19164095
2013 A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system. Cytokine & growth factor reviews 237 23587803
2006 Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proceedings of the National Academy of Sciences of the United States of America 223 16966615
2005 Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. European journal of immunology 205 15832291
2005 Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome. Arthritis and rheumatism 197 15934082
1998 The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proceedings of the National Academy of Sciences of the United States of America 181 9653165
2019 The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. Journal of molecular cell biology 172 30239845
1999 The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. The Journal of experimental medicine 159 10523616
2016 SLC Transporters: Structure, Function, and Drug Discovery. MedChemComm 152 27672436
2004 CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clinical cancer research : an official journal of the American Association for Cancer Research 150 15073111
1999 Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochemical and biophysical research communications 145 10441476
2020 Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion. Clinical cancer research : an official journal of the American Association for Cancer Research 144 32816947
2011 Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. The EMBO journal 139 21441897
2000 Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. Journal of immunology (Baltimore, Md. : 1950) 139 10754285
2011 Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis and rheumatism 124 21225692
2020 CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients. Gastroenterology 120 32330476
2000 Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. Journal of immunology (Baltimore, Md. : 1950) 119 10925282
2003 The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 116 14517790
2015 The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis. Molecular cancer 115 25744065
2004 The role of CCL21 in recruitment of T-precursor cells to fetal thymi. Blood 112 15358618
2020 The Role of the SLC Transporters Protein in the Neurodegenerative Disorders. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 100 32329299
2005 The lymphoid chemokine CCL21 costimulates naive T cell expansion and Th1 polarization of non-regulatory CD4+ T cells. Cellular immunology 98 15919372
2012 Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. Journal of drug targeting 94 22994411
2019 A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. Nature 92 31875850
2017 Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI insight 91 29263302
2016 SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. The Biochemical journal 90 27118869
2020 CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. Journal of cellular physiology 86 32017846
2020 Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis. Cell chemical biology 81 32386596
2020 The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression. Cancers 79 32340161
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2009 CCR7-CCL19/CCL21-regulated dendritic cells are responsible for effectiveness of sublingual vaccination. Journal of immunology (Baltimore, Md. : 1950) 75 19454681
1999 CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56(+)CD16(-) NK cells and late stage lymphoid progenitors. Cellular immunology 72 10222066
2009 RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models. The Journal of pharmacy and pharmacology 70 19405996
2003 SLC/CCL21-mediated anti-tumor responses require IFNgamma, MIG/CXCL9 and IP-10/CXCL10. Molecular cancer 66 12740040
2012 Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis. Arthritis and rheumatism 63 22392503
2014 Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. Frontiers in cellular neuroscience 62 25147499
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2021 The role of SLC transporters for brain health and disease. Cellular and molecular life sciences : CMLS 60 34971415
2020 CCL21-loaded 3D hydrogels for T cell expansion and differentiation. Biomaterials 60 32829146
2019 The RNA-Binding Protein YBX3 Controls Amino Acid Levels by Regulating SLC mRNA Abundance. Cell reports 60 31189097
2009 CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway. Blood 58 19451552
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1999 SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation. Journal of leukocyte biology 53 10496316
2015 CCL21-CCR7 promotes the lymph node metastasis of esophageal squamous cell carcinoma by up-regulating MUC1. Journal of experimental & clinical cancer research : CR 52 26667143
2011 ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation. Blood 52 21865343
2015 CCL21/CCR7 enhances the proliferation, migration, and invasion of human bladder cancer T24 cells. PloS one 51 25798926
2016 Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation. Oncotarget 50 27144525
2002 Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases. Blood 49 12393410
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2002 Low-molecular-weight heparins inhibit CCL21-induced T cell adhesion and migration. The Journal of pharmacology and experimental therapeutics 46 12065729
2007 CCL21 induces extensive intratumoral immune cell infiltration and specific anti-tumor cellular immunity. International journal of oncology 43 17273764
2015 CCL21 Facilitates Chemoresistance and Cancer Stem Cell-Like Properties of Colorectal Cancer Cells through AKT/GSK-3β/Snail Signals. Oxidative medicine and cellular longevity 41 27057280
2006 Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model. The Journal of allergy and clinical immunology 41 16675330
2019 Nonionic surfactants modulate the transport activity of ATP-binding cassette (ABC) transporters and solute carriers (SLC): Relevance to oral drug absorption. International journal of pharmaceutics 40 31125713
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2010 CCR7/CCL21 migration on fibronectin is mediated by phospholipase Cgamma1 and ERK1/2 in primary T lymphocytes. The Journal of biological chemistry 35 20889506
2023 In silico analysis of the solute carrier (SLC) family in cancer indicates a link among DNA methylation, metabolic adaptation, drug response, and immune reactivity. Frontiers in pharmacology 33 37397501
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2011 CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model. Cancer gene therapy 31 21997231
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2016 Decreased expression of SLC 39A14 is associated with tumor aggressiveness and biochemical recurrence of human prostate cancer. OncoTargets and therapy 29 27471394
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2014 CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions. Drug design, development and therapy 27 25473269
2009 CCL21-induced calcium transients and proliferation in primary mouse astrocytes: CXCR3-dependent and independent responses. Brain, behavior, and immunity 27 19401230
2023 CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity. Journal for immunotherapy of cancer 26 37730274
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2015 Polarized location of SLC and ABC drug transporters in monolayer-cultured human hepatocytes. Toxicology in vitro : an international journal published in association with BIBRA 26 25862123
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2018 Fluorescently Tagged CCL19 and CCL21 to Monitor CCR7 and ACKR4 Functions. International journal of molecular sciences 25 30518137
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2015 Anti-CCL21 antibody attenuates infarct size and improves cardiac remodeling after myocardial infarction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 26393504
2014 CCL21 and IFNγ recruit and activate tumor specific T cells in 3D scaffold model of breast cancer. Anti-cancer agents in medicinal chemistry 23 24237220
2014 Enhanced antitumor immunity is elicited by adenovirus-mediated gene transfer of CCL21 and IL-15 in murine colon carcinomas. Cellular immunology 23 24838092
2023 SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration. Frontiers in oncology 22 36776327
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2012 oxLDL downregulates the dendritic cell homing factors CCR7 and CCL21. Mediators of inflammation 22 22619482
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2019 Unraveling 'The Cancer Genome Atlas' information on the role of SLC transporters in anticancer drug uptake. Expert review of clinical pharmacology 21 30744443
2018 CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells. Journal of leukocyte biology 21 29768676
2016 Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers. Drug metabolism and disposition: the biological fate of chemicals 21 27044799
2015 SAMP1/YitFc mice develop ileitis via loss of CCL21 and defects in dendritic cell migration. Gastroenterology 21 25620669
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2014 Increased CCL19 and CCL21 levels promote fibroblast ossification in ankylosing spondylitis hip ligament tissue. BMC musculoskeletal disorders 20 25260647
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