Affinage

CCL22

C-C motif chemokine 22 · UniProt O00626

Length
93 aa
Mass
10.6 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL22 is a CC chemokine that functions as a selective chemoattractant for chronically activated and Th2 memory CD4+ T lymphocytes, signaling through its receptor CCR4, which it shares with CCL17 (PMID:9312138, PMID:9794440). CCR4 engagement triggers Ca2+ mobilization and drives directional migration through a phospholipase C/diacylglycerol/PKCδ-dependent pathway that is separable from IP3-mediated Ca2+ release (PMID:16614259). CCL22 is also a potent and rapid inducer of CCR4 internalization via lipid raft- and clathrin-dependent mechanisms that produce functional desensitization, distinguishing it from CCL17 which does not internalize the receptor (PMID:14971049). The principal in vivo role of CCL22 is to recruit CCR4+ regulatory T cells and orchestrate DC–Treg contacts: CCL22-deficient mice show exaggerated vaccination responses and improved tumor control, while CCL22 delivery recruits Tregs to autoimmune and inflammatory sites to enforce tolerance (PMID:30910796, PMID:21737880, PMID:25264308). This Treg-recruiting axis is repeatedly co-opted in cancer, where tumor cells, dendritic cells, NK cells, and tumor-associated macrophages are induced to secrete CCL22 by signals including IL-1, TNF-α/IFN-γ, and TGF-β, thereby drawing immunosuppressive Tregs into tumors (PMID:19244125, PMID:19234170, PMID:21852386, PMID:30928379). CCL22 expression is transcriptionally controlled by NF-κB together with STAT/AP-1 elements and is constitutively driven in lymphoid organs by T cell-derived GM-CSF acting on dendritic cells (PMID:11352815, PMID:14747532, PMID:32907996). In germinal centers, CD40-stimulated upregulation of CCL22 by GC B cells in proportion to antigen affinity recruits follicular helper T cells to drive antibody affinity maturation (PMID:33597749). Downstream of CCR4 in macrophages, CCL22 engages DGKα as a signaling adaptor that assembles a DGKα/FAK signalosome to activate FAK/AKT (PMID:35962191). Somatic gain-of-function mutations in CCL22 that impair β-arrestin recruitment cause biased CCR4 signaling with reduced receptor internalization and enhanced chemotaxis, underlying a subset of chronic lymphoproliferative disorder of NK cells (PMID:35513723).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Establishing that a newly cloned CC chemokine selectively attracts activated T cells defined CCL22's target-cell specificity, distinguishing it from chemokines acting on myeloid cells.

    Evidence Molecular cloning from activated macrophage cDNA with Ca2+ flux and in vitro chemotaxis across multiple leukocyte types

    PMID:9312138

    Open questions at the time
    • Receptor not yet identified
    • Signaling pathway downstream of Ca2+ flux unknown
  2. 1998 High

    Identifying CCR4 as the shared receptor for CCL22 and CCL17 and linking CCL22 to Th2 memory cells defined the receptor axis and cytokine regulation of its production.

    Evidence Ca2+ flux cross-desensitization, T cell subset chemotaxis, and cytokine stimulation of producer cells

    PMID:9794440

    Open questions at the time
    • Intracellular signaling downstream of CCR4 not dissected
    • Receptor pairing with atypical receptors unaddressed
  3. 2001 Medium

    Identifying NF-κB-dependent transcription and N-terminally truncated inactive CCL22 forms established both the inducible expression control and a post-translational negative-feedback mechanism.

    Evidence ELISA, mass spectrometry of DC supernatants, NF-κB inhibition, and polarized epithelial chemotaxis assays

    PMID:11241286 PMID:11352815

    Open questions at the time
    • Protease generating truncated forms not identified
    • Promoter elements not yet mapped
  4. 2004 High

    Showing that CCL22 (but not CCL17) drives rapid clathrin/lipid raft-dependent CCR4 internalization and desensitization revealed ligand-biased receptor regulation that tunes chemotactic responsiveness.

    Evidence Flow cytometry internalization assays with pharmacological inhibitors and chemotaxis recovery on human Th2 cells

    PMID:14971049

    Open questions at the time
    • β-arrestin dependence not directly tested at this stage
    • Structural basis of ligand bias unknown
  5. 2004 High

    Promoter dissection identifying specific NF-κB and AP-1 sites driven by viral LMP1 defined the cis-regulatory architecture of CCL22 transcription.

    Evidence CCL22 promoter-reporter constructs with pathway inhibitors in B cells

    PMID:14747532

    Open questions at the time
    • Endogenous (non-viral) activators of these sites not fully mapped here
    • Cell-type-specific enhancer usage unaddressed
  6. 2006 High

    Separating Ca2+ signaling from migration and identifying PKCδ Thr505 phosphorylation defined the molecular pathway converting CCR4 engagement into directional movement.

    Evidence Pharmacological dissection of PLC/PKC/IP3R/PI3K with Ca2+ imaging and chemotaxis in CEM and primary Th2 cells

    PMID:16614259

    Open questions at the time
    • Link between PKCδ and cytoskeletal effectors not defined
    • Connection to later DGKα/FAK signalosome not established at this time
  7. 2009 High

    Genetic loss of CCL22 in mice and Treg recruitment assays established the in vivo physiological role of CCL22 in DC–Treg contact and tolerance, with consequences for vaccination and tumor immunity.

    Evidence CCL22-deficient and CCR4-KO mouse models, vaccination, tumor challenge, IDO induction, and Treg migration assays

    PMID:19244125 PMID:19318474 PMID:19843945 PMID:30910796

    Open questions at the time
    • Quantitative contribution of CCL22 versus CCL17 in vivo not fully separated
    • Downstream tolerance mediators only partially mapped
  8. 2011 High

    Demonstrating that islet or NK-cell-derived CCL22 recruits Tregs to confer tissue protection established the therapeutic and tumor-microenvironment relevance of the CCL22→Treg axis.

    Evidence AAV CCL22 gene delivery with anti-CD25 Treg depletion in NOD mice and NK depletion/CCL22 neutralization in tumor models

    PMID:19234170 PMID:21737880

    Open questions at the time
    • Cellular source hierarchy across tissues not unified
    • Duration and reversibility of Treg recruitment unaddressed
  9. 2016 Medium

    Mapping the cytokine inputs (IL-1, TNF-α, IFN-γ, TGF-β/miR-34a, type I IFN) that induce or suppress CCL22 across tumor cells, DCs, and macrophages defined the regulatory network governing intratumoral CCL22 levels.

    Evidence Co-culture, cytokine neutralization, siRNA, miR-34a manipulation, and CCL22 overexpression rescue across multiple tumor systems

    PMID:21852386 PMID:22975373 PMID:26432403 PMID:27757295

    Open questions at the time
    • Relative weighting of inducers in human tumors unclear
    • Single-lab findings for several individual axes
  10. 2020 Medium

    Identifying T cell-derived GM-CSF as the required inducer of constitutive DC-derived CCL22 and identifying ACKR4 as an additional receptor refined both the homeostatic source control and the receptor repertoire of CCL22.

    Evidence DC–T cell coculture, Rag1-KO with adoptive transfer and GM-CSF reconstitution; systematic 43-chemokine β-arrestin screen against ACKR4

    PMID:32480426 PMID:32907996

    Open questions at the time
    • Functional consequence of ACKR4 partial agonism in vivo unknown
    • GM-CSF signaling pathway to CCL22 promoter not mapped
  11. 2021 High

    B cell-specific ablation in germinal centers showed CCL22 recruits TFH help in proportion to B cell affinity, establishing a positive-feedback circuit driving antibody affinity maturation.

    Evidence Conditional B cell CCL22/CCL17 knockout, competitive GC experiments, TFH imaging, and plasma cell quantification

    PMID:33597749

    Open questions at the time
    • Contribution of CCL22 alone versus combined with CCL17 not fully separated
    • Affinity-to-CCL22 transcriptional coupling mechanism unknown
  12. 2022 High

    Biochemical reconstitution of a DGKα/FAK signalosome and discovery of β-arrestin-impairing gain-of-function mutations defined a downstream effector pathway and a disease mechanism of biased CCR4 signaling.

    Evidence Co-IP, phospho-site mapping, DGKα siRNA, and xenografts; genomic sequencing with β-arrestin, internalization, chemotaxis, and IL-15 transgenic mouse assays

    PMID:35513723 PMID:35962191

    Open questions at the time
    • Whether DGKα/FAK operates in T cells as in macrophages unaddressed
    • Structural basis linking mutations to β-arrestin loss not resolved
  13. 2024 Medium

    Linking CCL22/DGKα to phosphatidic acid-mediated NOX4 suppression and NF-κB-driven ABC transporter upregulation defined a mechanism of chemoresistance downstream of CCL22 signaling.

    Evidence Lipid profiling, NOX4/ROS assays, NF-κB reporter, ABC transporter expression, and DGKα siRNA xenografts

    PMID:38387281

    Open questions at the time
    • Generalizability beyond ESCC unknown
    • Relative contribution of the two branches to resistance not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCL22 transcriptional output is quantitatively coupled to antigen affinity in GC B cells, and whether ACKR2/ACKR4 scavenging shapes CCL22 gradients in vivo, remain open.
  • No structural model of CCL22–CCR4/ACKR4 complexes
  • In vivo role of atypical receptor binding uncharacterized
  • Mechanism coupling B cell affinity to CCL22 levels unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1500931 Cell-Cell communication 4 R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2
Partners
ACKR4CCR4DGKA

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CCL22 (STCP-1) is a CC chemokine that induces Ca2+ mobilization and acts as a potent chemoattractant specifically for chronically activated T lymphocytes, but not for monocytes, neutrophils, eosinophils, or resting T lymphocytes. Molecular cloning from activated macrophage cDNA library; Ca2+ mobilization assay; in vitro chemotaxis assay The Journal of biological chemistry High 9312138
1998 CCL22 (STCP-1) acts specifically on Th2 memory CD4+ lymphocytes via CCR4; TARC (CCL17) and STCP-1 share CCR4 as a common receptor, demonstrated by cross-desensitization in Ca2+ flux experiments. CCL22 is produced constitutively by dendritic cells, B cells, and macrophages, and its production is upregulated by IL-4 and IL-13 and inhibited by IL-10. Ca2+ flux desensitization assay; in vitro T cell subset chemotaxis; cytokine stimulation of producer cells with ELISA Journal of immunology High 9794440
2001 Dendritic cells are the predominant source of CCL22 among leukocytes; DC maturation signals (LPS, IL-1, TNF, CD40L, bacteria/yeast recognition) dramatically increase CCL22 production. Mass spectrometry of DC supernatants identified N-terminally truncated forms CCL22(3-69), CCL22(5-69), and CCL22(7-69) that do not recognize CCR4, suggesting a negative feedback regulatory mechanism. ELISA; mass spectrometry of DC supernatants; in vitro DC stimulation assays; immunohistochemistry European journal of immunology High 11241286
2001 CCL22 and its receptor CCR4 are involved in the formation of T lymphocyte–dendritic cell clusters in inflamed skin and secondary lymphoid tissue; CCL22 is produced by DCs in T cell zones, and CCR4 is expressed on approximately one-third of CD4+ T cells in inflamed skin. RT-PCR; immunohistochemistry; cell-type identification in human tissue The American journal of pathology Medium 11290544
2001 Intestinal epithelial cells constitutively produce CCL22, and NF-κB activation is required for CCL22 expression in response to proinflammatory cytokines or enteroinvasive bacteria. CCL22 secreted from the basolateral side of polarized epithelial cells induces CCR4+ T cell chemotaxis. RT-PCR; ELISA; NF-κB inhibition assay; polarized epithelial cell chemotaxis assay American journal of physiology. Gastrointestinal and liver physiology Medium 11352815
2002 CD40 ligation of CLL B cells induces CCL22 mRNA expression and protein secretion; secreted CCL22 recruits activated CD4+CD40L+ T cells via CCR4, and this migration is abrogated by anti-CCL22 antibodies. RT-PCR; ELISA; neutralizing antibody migration assay; immunohistochemistry European journal of immunology Medium 11981828
2002 IFN-γ stimulates primary epidermal keratinocytes to express CCL22 mRNA and protein; CCL22 immunoreactivity is present in the epidermal layer of atopic dermatitis skin, suggesting post-transcriptional regulation distinguishes CCL22 from CCL17 production in these cells. ELISA; RT-PCR; immunohistochemistry of human AD skin; primary keratinocyte stimulation International immunology Medium 12096036
2002 Activated microglia produce bioactive CCL22 that induces chemotaxis of Th2 but not Th1 cells; CCL22 and CCR4 mRNAs are expressed in the CNS of EAE mice, with CCL22 produced by CNS-infiltrating leukocytes and intraparenchymal microglia. In vitro microglia activation; Th1/Th2 chemotaxis assay; immunohistochemistry; RT-PCR in EAE model Journal of neuroimmunology Medium 12225884
2004 CCL22 is a potent and rapid inducer of CCR4 internalization on human Th2 cells via lipid raft- and clathrin-coated pit-dependent mechanisms, independent of G protein coupling. CCL17 does not induce CCR4 internalization. CCR4 internalization leads to functional desensitization, which is reversed by receptor recycling to restore chemotactic responsiveness. Flow cytometry CCR4 internalization assay; pharmacological inhibitors (lipid raft disruption, clathrin inhibition, G protein uncoupling); chemotaxis recovery assays on human Th2 cells European journal of immunology High 14971049
2004 Latent membrane protein 1 (LMP1) of EBV induces CCL22 expression in B cells via NF-κB and ATF2/p38 signaling pathways; transfection assays with CCL22 promoter-reporter constructs identified two NF-κB sites and one AP-1 site as required for LMP1-mediated CCL22 promoter activation. Transient transfection reporter assay with CCL22 promoter constructs; pathway inhibitors (BAY11-7082, SB202190); RT-PCR; ELISA Journal of virology High 14747532
2006 CCL22 and CCL17 stimulate T cell migration via CCR4 through a phospholipase C (PLC)- and diacylglycerol/novel PKC isoform-dependent mechanism; PLC inhibition blocks both Ca2+ mobilization and chemotaxis. Specifically, CCL22 stimulates phosphatidylinositol-3 kinase-independent phosphorylation of PKCδ at Thr505, associated with increased catalytic activity. Inhibition of IP3 receptor-mediated Ca2+ release blocks Ca2+ responses but not directional migration. Pharmacological inhibitors of PLC, PKC isoforms, IP3R, PI3K; Ca2+ imaging; chemotaxis assay in CEM cells and primary Th2 cells; PKCδ phosphorylation by western blot Journal of leukocyte biology High 16614259
2006 RANKL stimulation induces CCL22 production in differentiating osteoclasts; CCL22 stimulates migration and invasion of CCR4-expressing lung cancer cells (SBC-5) and activates phosphorylation of Akt and ERK in these cells. RANKL stimulation of RAW264.7 and mouse bone marrow cells; RT-PCR; ELISA; migration assay; western blot (pAkt, pERK); immunohistochemistry of bone metastasis lesions Clinical & experimental metastasis Medium 16821125
2008 HCMV UL144 protein activates NF-κB to transcriptionally induce CCL22; although viral IE86 can block NF-κB binding to synthetic promoters, it is unable to block UL144-mediated activation of the CCL22 promoter, with CREB binding to the CCL22 promoter implicated in this resistance. Promoter-reporter transfection assays; co-expression of UL144 and IE86; EMSA/DNA binding analysis Journal of virology Medium 18287226
2009 CCL22 promotes formation of DC–regulatory T cell contacts through CCR4 in lymph nodes; CCL22 expression by DCs is required for proper Treg–DC interaction. In CCL22-deficient mice, vaccination leads to excessive T cell responses, and tumor-bearing CCL22-deficient mice show prolonged survival upon vaccination. CCL22-deficient mouse model; vaccination assays; tumor challenge; flow cytometry; live imaging of cell-cell contacts The Journal of experimental medicine High 30910796
2009 CCL22 produced by tumor cells recruits CCR4-expressing regulatory T cells into breast tumor-associated lymphoid infiltrates; blood Tregs selectively express CCR4, and CCR4 is downregulated on tumor-infiltrating Tregs indicating receptor engagement by CCL22. Immunohistochemistry; flow cytometry; in vitro migration assay; CCR4 expression analysis on Tregs Cancer research Medium 19244125
2009 CCL22 level in malignant pleural effusion is chemotactic for CD4+CD25+FoxP3+ regulatory T cells; this chemotactic activity is partially blocked by anti-CCL22 antibody but not anti-CCL17 antibody. Intrapleural administration of CCL22 induces progressive influx of Tregs into the pleural space in vivo. In vitro Transwell migration assay with neutralizing antibody; in vivo intrapleural CCL22 administration; ELISA; flow cytometry Clinical cancer research Medium 19318474
2009 In mesenteric lymph node DCs, phagocytosis of autologous apoptotic cells induces CCL22 expression; CCL22/CCR4 axis facilitates DC–Treg interactions that promote IDO expression in DCs via CTLA-4/B7. CCR4-deficient mice show markedly reduced IDO expression in MLN-DCs. CCR4-KO mouse model; apoptotic cell phagocytosis assay; IDO activity measurement; CTLA-4 conditional deletion in Tregs; colocalization analysis Journal of immunology Medium 19843945
2009 TNF-α/IFN-γ-induced CCL22 production in HaCaT keratinocytes is mediated via NF-κB and STAT1 activation, with p38 MAPK acting upstream to regulate both pathways. The adenylyl cyclase–cAMP system suppresses CCL22 production by inhibiting NF-κB activation through the p38 MAPK pathway. Western blot; RT-PCR; ELISA; pharmacological inhibitors (p38, NF-κB, cAMP analogs, adenylyl cyclase activator) Molecular immunology Medium 19371952
2010 CCL22 controls EAE development by regulating CD11b+Ly6Chi macrophage accumulation and effector function; anti-CCL22 neutralization reduces CNS macrophage infiltration and shifts macrophage cytokine expression from TNF-dominated (M1) to IL-10-dominated (M2) phenotype, both in vivo and in in vitro macrophage cultures treated with CCL22. Anti-CCL22 neutralizing antibody in EAE model; adoptive T cell transfer; flow cytometry; in vitro macrophage culture with CCL22 Journal of leukocyte biology Medium 20940325
2011 Islet expression of CCL22 recruits endogenous Tregs to pancreatic islets and prevents autoimmune diabetes in NOD mice; the protective effect is abrogated by CD25-specific antibody depletion of Tregs. CCL22-mediated protection increases TGF-β levels in CD4+ T cells near islets and decreases autoreactive CD8+ T cells. AAV-mediated CCL22 gene delivery to islets; Treg depletion with anti-CD25 antibody; flow cytometry; cytokine measurement The Journal of clinical investigation High 21737880
2011 NK cells secrete CCL22 in the tumor microenvironment and are the predominant cellular source responsible for CCL22-dependent selective recruitment of CCR4+ regulatory T cells; NK cell depletion from lung tissue significantly reduces CCL22 secretion, and CCL22 neutralization reduces selective Treg recruitment. Immunomagnetic cell isolation; FACS; flow cytometry; NK cell depletion; CCL22 neutralization; migration assay Journal of immunology Medium 19234170
2011 CCL22 production by breast tumor cells is controlled by innate immune cell-derived signals: monocyte-derived IL-1β and TNF-α, combined with IFN-γ from NK cells, drive CCL22 secretion from tumor cells. Monocyte depletion or cytokine neutralization attenuates CCL22 secretion. Co-culture of breast tumor cell lines with PBMCs; monocyte depletion; cytokine neutralization; NK cell activation assays; ELISA Cancer research Medium 21852386
2012 TGF-β suppresses miR-34a expression, leading to enhanced CCL22 production which recruits Treg cells to facilitate immune escape in HBV-associated hepatocellular carcinoma with portal vein tumor thrombus. TGF-β–miR-34a–CCL22 forms a regulatory axis. miRNA expression profiling; miR-34a overexpression/knockdown; TGF-β stimulation; ELISA; Treg migration assay Cancer cell Medium 22975373
2015 IL-4-driven CCL22 production by local cells is required for CCR4+ Treg migration to osteolytic lesions in experimental periodontitis; CCR4-KO mice and CCL22 blockade both increase bone loss and proinflammatory cytokines. Exogenous CCL22 delivered via PLGA microparticles restores Treg migration and bone loss arrest in IL-4-KO mice that lack endogenous CCL22. CCR4-KO mice; anti-CCL22 antibody blockade; adoptive Treg transfer; PLGA microparticle CCL22 delivery in IL-4-KO mice; flow cytometry Journal of bone and mineral research High 25264308
2015 Type I IFN induced by TLR or RIG-I ligands suppresses intratumoral CCL22 levels, thereby blocking Treg immigration into tumors. Stable overexpression of CCL22 abrogates the anti-tumor effects of RLR/TLR ligand treatment, confirming that CCL22 suppression is the key downstream effector of type I IFN's Treg-blocking activity. In vivo TLR/RLR ligand treatment; CCL22 stable overexpression in tumors; flow cytometry of tumor-infiltrating Tregs; ELISA Cancer research Medium 26432403
2016 Cancer cell-derived IL-1α induces CCL22 production by intratumoral dendritic cells (not by cancer cells themselves); this is prevented by the IL-1 receptor antagonist anakinra or by IL-1α siRNA knockdown in tumor cells, leading to suppression of Treg migration. In vitro PBMC co-culture with tumor cells; IL-1 receptor antagonist; IL-1α siRNA knockdown; ELISA; Treg migration assay Oncoimmunology Medium 27757295
2016 CCL22-specific T cells recognizing a HLA-A2-restricted signal-peptide-derived epitope can kill CCL22-expressing cancer cells and acute monocytic leukemia cells in a CCL22 expression-dependent manner; spontaneous CCL22-specific T cell responses exist in cancer patients. Peptide epitope stimulation of PBMCs; cytotoxicity assay; ELISPOT; tetramer enrichment/depletion; CCL22-dependent killing validation Oncoimmunology Medium 27999757
2019 TAM-derived TGF-β induces CCL22 expression in macrophages via c-Fos; CCL22 recruits Tregs into malignant pleural effusion; Treg-secreted IL-8 further induces TGF-β production from TAMs, creating a positive feedback immunosuppressive loop. Western blot for c-Fos; TGF-β stimulation of macrophages; CCL22 neutralization; Treg migration assay; IL-8 measurement Cancer letters Medium 30928379
2019 M2 macrophage-derived CCL22 promotes resistance of colorectal cancer cells to 5-FU by activating the PI3K/AKT pathway, inducing EMT, and inhibiting caspase-mediated apoptosis; neutralizing anti-CCL22 antibody abolishes these effects. M2 macrophage conditioned medium; neutralizing anti-CCL22 antibody; western blot (PI3K/AKT, EMT markers, caspase); cell migration/invasion assay; apoptosis assay OncoTargets and therapy Medium 31114248
2020 Constitutive CCL22 expression in secondary lymphoid organs requires T cell-derived GM-CSF: DCs alone cannot produce CCL22, but coculture with T cells or T cell supernatants induces CCL22 secretion. Rag1-/- mice (lacking T cells) have low lymphoid CCL22, restored by adoptive T cell transfer or GM-CSF administration. DC-T cell coculture; T cell supernatant fractionation; cytokine neutralization; Rag1-KO mouse with adoptive transfer; GM-CSF administration Journal of immunology High 32907996
2021 Upon CD40 stimulation, GC B cells upregulate CCL22 (and CCL17); CCL22 engages CCR4 on follicular helper T (TFH) cells to attract them, promoting productive T cell help. Higher-affinity GC B cells express higher CCL22 levels, creating a feedback loop that preferentially recruits TFH help. Ablation of CCL22 (and CCL17) in B cells results in inefficient affinity maturation, reduced GC participation, and fewer bone-marrow plasma cells. Conditional B cell-specific CCL22/CCL17 knockout mice; competitive GC experiments; TFH cell imaging; GC B cell affinity analysis; plasma cell quantification Nature High 33597749
2021 Toxoplasma gondii effector protein GRA28 is secreted into host cell nuclei and is required for CCL22 induction in human placental cells and monocytes; parasites lacking GRA28 produce reduced CCL22 and are impaired in dissemination in vivo. GRA28 deletion mutant parasite; GRA28 nuclear localization by imaging; CCL22 ELISA in human placental cells, monocyte lines, mouse immune cells in vitro and in vivo; parasite dissemination assay mBio Medium 34781732
2020 CCL22 acts as a potent partial agonist at ACKR4 (atypical chemokine receptor 4), recruiting β-arrestin; this was identified in a systematic screen of all 43 human chemokines using a sensitive β-arrestin recruitment assay, extending the known receptor repertoire of CCL22 beyond CCR4 and ACKR2. β-arrestin recruitment assay; systematic screen of 43 chemokines against ACKR4 Journal of leukocyte biology Medium 32480426
2022 Somatic gain-of-function mutations in CCL22 are the hallmark of a subset of chronic lymphoproliferative disorder of NK cells (CLPD-NK); these mutations cause ligand-biased GPCR signaling by impairing β-arrestin recruitment to CCR4, reducing receptor internalization, resulting in increased cell chemotaxis in vitro and enhanced NK cell proliferation in vivo in transgenic IL-15 mice. Genomic sequencing; β-arrestin recruitment assay; receptor internalization assay; in vitro chemotaxis assay; in vivo transgenic mouse model Nature genetics High 35513723
2022 TAM-derived CCL22 activates diacylglycerol kinase α (DGKα) which acts as a signaling adaptor linking CCR4 to FAK; CCL22/CCR4 signaling activates intracellular Ca2+/PLC-γ1 axis to stimulate DGKα phosphorylation at Tyr335 and promotes DGKα translocation to the plasma membrane to assemble a DGKα/FAK signalosome, activating the FAK/AKT pathway. Co-immunoprecipitation; western blot (phospho-FAK, phospho-DGKα); PLC-γ1 inhibition; DGKα siRNA; Ca2+ imaging; subcellular fractionation; in vivo xenograft model with DGKα siRNA Cellular & molecular immunology High 35962191
2024 TAM-derived CCL22 activates DGKα to produce phosphatidic acid (PA), suppressing NOX4 activity and blocking cisplatin-induced ROS overproduction; CCL22 also activates DGKα/NF-κB to upregulate ABC transporters (ABCG4, ABCA3, ABCA5), lowering intratumoral cisplatin concentration. Both mechanisms contribute to cisplatin resistance in ESCC. Lipid profiling (PA measurement); NOX4 activity assay; ROS measurement; NF-κB reporter; ABC transporter RT-PCR/western blot; DGKα siRNA cholesterol-conjugate in vivo; xenograft models Drug resistance updates Medium 38387281
2021 In vitro, CCL22 promotes polarization of tumor-associated macrophages (TAMs) toward the M2a macrophage phenotype (CD206high) in a cervical cancer co-culture model; CCL22 regulates CD206 expression as assessed by flow cytometry. Co-culture system; CCL22 modulation; flow cytometry for macrophage subset markers Cells Low 35805111

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer research 588 19244125
2012 TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer cell 473 22975373
2008 CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. International journal of cancer 317 18224687
2001 Dendritic cells as a major source of macrophage-derived chemokine/CCL22 in vitro and in vivo. European journal of immunology 209 11241286
2002 Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. European journal of immunology 207 11981828
1998 STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13. Journal of immunology (Baltimore, Md. : 1950) 206 9794440
2019 CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. The Journal of experimental medicine 205 30910796
2019 Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion. Cancer letters 156 30928379
2004 Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. Journal of dermatological science 156 15113590
2004 Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus. Journal of virology 149 14747532
2002 IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. International immunology 136 12096036
2009 Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 125 19630858
2017 The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity. International journal of molecular sciences 108 29099057
2011 Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells. Cancer research 106 21852386
2017 Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis. Oncotarget 102 28039457
2004 Dominance of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization and internalization on human Th2 cells. European journal of immunology 98 14971049
2011 Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets. The Journal of clinical investigation 90 21737880
2002 Induction of macrophage-derived chemokine/CCL22 expression in experimental autoimmune encephalomyelitis and cultured microglia: implications for disease regulation. Journal of neuroimmunology 87 12225884
2011 Casuarinin suppresses TARC/CCL17 and MDC/CCL22 production via blockade of NF-κB and STAT1 activation in HaCaT cells. Biochemical and biophysical research communications 85 22227193
2006 Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells. Immunology 85 16556265
2019 M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling. OncoTargets and therapy 84 31114248
2015 IL-4/CCL22/CCR4 axis controls regulatory T-cell migration that suppresses inflammatory bone loss in murine experimental periodontitis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 84 25264308
2016 Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells. Oncoimmunology 83 27757295
2001 Macrophage-derived chemokine (MDC/CCL22) and CCR4 are involved in the formation of T lymphocyte-dendritic cell clusters in human inflamed skin and secondary lymphoid tissue. The American journal of pathology 83 11290544
1997 Molecular cloning and functional characterization of a novel CC chemokine, stimulated T cell chemotactic protein (STCP-1) that specifically acts on activated T lymphocytes. The Journal of biological chemistry 83 9312138
2006 RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4. Clinical & experimental metastasis 80 16821125
2009 Macrophage derived chemokine (CCL22), thymus and activation-regulated chemokine (CCL17), and CCR4 in idiopathic pulmonary fibrosis. Respiratory research 76 19715610
2009 CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 76 20002703
2009 CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clinical cancer research : an official journal of the American Association for Cancer Research 74 19318474
2009 NK-dependent increases in CCL22 secretion selectively recruits regulatory T cells to the tumor microenvironment. Journal of immunology (Baltimore, Md. : 1950) 73 19234170
2001 Stem cell factor and igE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 73 11339505
2015 Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer research 70 26432403
2010 Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection. Journal of hepatology 69 21129807
2009 Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Cytokine 69 19942450
2009 The adenylyl cyclase-cAMP system suppresses TARC/CCL17 and MDC/CCL22 production through p38 MAPK and NF-kappaB in HaCaT keratinocytes. Molecular immunology 68 19371952
2003 Differential expression of thymus- and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) by human fibroblasts from cornea, skin, and lung. The Journal of allergy and clinical immunology 67 12642832
2015 CCL22 to Activate Treg Migration and Suppress Depigmentation in Vitiligo. The Journal of investigative dermatology 66 25634358
2012 Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma. International journal of cancer 66 23180648
2016 Fucoidan inhibits CCL22 production through NF-κB pathway in M2 macrophages: a potential therapeutic strategy for cancer. Scientific reports 65 27775051
2016 CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment. Oncoimmunology 65 27999757
2004 CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis. The European respiratory journal 65 15293604
2009 Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. Journal of immunology (Baltimore, Md. : 1950) 61 19843945
2001 Production of MDC/CCL22 by human intestinal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 57 11352815
2021 Affinity-coupled CCL22 promotes positive selection in germinal centres. Nature 55 33597749
2018 CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjögren's Syndrome. Frontiers in immunology 55 30467506
2005 Elevated expression of TARC (CCL17) and MDC (CCL22) in models of cigarette smoke-induced pulmonary inflammation. Biochemical and biophysical research communications 55 15993846
2016 Higher circulating levels of chemokines CXCL10, CCL20 and CCL22 in patients with ischemic heart disease. Cytokine 53 27152707
2015 CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer immunology, immunotherapy : CII 53 25754123
2004 Role of CCR4 ligands, CCL17 and CCL22, during Schistosoma mansoni egg-induced pulmonary granuloma formation in mice. The American journal of pathology 53 15466387
2022 Tumor-associated macrophage (TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma (ESCC). Cellular & molecular immunology 51 35962191
2003 Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22. European cytokine network 51 14715413
2019 Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 49 31134686
2020 CCL22 Signaling in the Tumor Environment. Advances in experimental medicine and biology 48 32060848
2014 The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots. Journal of translational medicine 47 25245466
2010 CCL22 regulates experimental autoimmune encephalomyelitis by controlling inflammatory macrophage accumulation and effector function. Journal of leukocyte biology 47 20940325
2019 Circ_0039569 promotes renal cell carcinoma growth and metastasis by regulating miR-34a-5p/CCL22. American journal of translational research 46 31497210
2008 Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder. Cancer science 46 18271928
2006 Expression of macrophage-derived chemokine (MDC)/CCL22 in human lung cancer. Cancer immunology, immunotherapy : CII 43 16453150
2016 Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma. Cancer research 41 27634754
2010 Titanium induced production of chemokines CCL17/TARC and CCL22/MDC in human osteoclasts and osteoblasts. Journal of biomedical materials research. Part A 41 19205012
2019 Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma. Frontiers in oncology 40 31616630
2014 Macrophage-derived chemokine (CCL22) is a novel mediator of lung inflammation following hemorrhage and resuscitation. Shock (Augusta, Ga.) 39 25136780
2010 The novel association of the chemokine CCL22 with abdominal aortic aneurysm. The American journal of pathology 39 20348247
2010 Sulforaphane suppresses TARC/CCL17 and MDC/CCL22 expression through heme oxygenase-1 and NF-κB in human keratinocytes. Archives of pharmacal research 39 21116791
2008 NF-kappaB-mediated activation of the chemokine CCL22 by the product of the human cytomegalovirus gene UL144 escapes regulation by viral IE86. Journal of virology 39 18287226
2006 Evidence that phospholipase-C-dependent, calcium-independent mechanisms are required for directional migration of T-lymphocytes in response to the CCR4 ligands CCL17 and CCL22. Journal of leukocyte biology 39 16614259
2015 Serum macrophage-derived chemokine/CCL22 levels are associated with glioma risk, CD4 T cell lymphopenia and survival time. International journal of cancer 38 25604093
2022 CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk. Nature genetics 37 35513723
2022 CCL22-Polarized TAMs to M2a Macrophages in Cervical Cancer In Vitro Model. Cells 35 35805111
2009 Targeted knock down of CCL22 and CCL17 by siRNA during DC differentiation and maturation affects the recruitment of T subsets. Immunobiology 34 19450895
2017 CCL2 conditionally determines CCL22-dependent Th2-accumulation during TGF-β-induced breast cancer progression. Immunobiology 33 29107385
2015 Cellular mechanisms of CCL22-mediated attenuation of autoimmune diabetes. Journal of immunology (Baltimore, Md. : 1950) 33 25740943
2014 Higher circulating levels of chemokine CCL22 in patients with breast cancer: evaluation of the influences of tumor stage and chemokine gene polymorphism. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 33 25722218
2009 Fluvastatin inhibits expression of the chemokine MDC/CCL22 induced by interferon-gamma in HaCaT cells, a human keratinocyte cell line. British journal of pharmacology 32 19594754
2015 S100B Up-Regulates Macrophage Production of IL1β and CCL22 and Influences Severity of Retinal Inflammation. PloS one 31 26204512
2022 CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment. Oncoimmunology 28 36052217
2022 EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22. PLoS pathogens 26 35025968
2022 circ_0004140 promotes LUAD tumor progression and immune resistance through circ_0004140/miR-1184/CCL22 axis. Cell death discovery 26 35396377
2021 Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse. mBio 26 34781732
2007 The role of CCL22/macrophage-derived chemokine in allergic rhinitis. Clinical immunology (Orlando, Fla.) 26 17911044
2024 Tumor-associated macrophage (TAM)-secreted CCL22 confers cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells via regulating the activity of diacylglycerol kinase α (DGKα)/NOX4 axis. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 25 38387281
2021 Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6. American journal of respiratory cell and molecular biology 25 33264064
2020 CCL22 signaling contributes to sorafenib resistance in hepatitis B virus-associated hepatocellular carcinoma. Pharmacological research 25 32278046
2020 Radiation-Enhanced Expression of CCL22 in Nasopharyngeal Carcinoma is Associated With CCR4+ CD8 T Cell Recruitment. International journal of radiation oncology, biology, physics 25 32428547
2004 LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22). Blood 25 15054038
2010 CCL22 is involved in the recruitment of CD4+CD25 high T cells into tuberculous pleural effusions. Respirology (Carlton, Vic.) 24 20337996
2022 LncRNA HOTAIR promotes proliferation, invasion and migration in NSCLC cells via the CCL22 signaling pathway. PloS one 23 35176085
2020 Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22. Journal of leukocyte biology 23 32480426
2015 CCL22 Prevents Rejection of Mouse Islet Allografts and Induces Donor-Specific Tolerance. Cell transplantation 23 26423995
2023 Pexidartinib synergize PD-1 antibody through inhibiting treg infiltration by reducing TAM-derived CCL22 in lung adenocarcinoma. Frontiers in pharmacology 21 36969873
2021 Macrophage CCL22 expression promotes lymphangiogenesis in patients with tongue squamous cell carcinoma via IL-4/STAT6 in the tumor microenvironment. Oncology letters 21 33777206
2020 Constitutive Expression of CCL22 Is Mediated by T Cell-Derived GM-CSF. Journal of immunology (Baltimore, Md. : 1950) 21 32907996
2019 Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate. Pathology 21 31445808
2020 Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function. Translational psychiatry 20 32179746
2015 Expression of CCL22 and Infiltration by Regulatory T Cells are Increased in the Decidua of Human Miscarriage Placentas. American journal of reproductive immunology (New York, N.Y. : 1989) 20 25922986
2007 Expression of chemokine receptor CCR4 and its ligands (CCL17 and CCL22) in murine contact hypersensitivity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20 18052724
2020 HBV promotes the recruitment of IL-17 secreting T cells via chemokines CCL22 and CCL17. Liver international : official journal of the International Association for the Study of the Liver 19 32187823
2016 Inhibitory effect of a histamine 4 receptor antagonist on CCL17 and CCL22 production by monocyte-derived Langerhans cells in patients with atopic dermatitis. The Journal of dermatology 19 26892271
2016 CCL22 and IL-37 inhibit the proliferation and epithelial-mesenchymal transition process of NSCLC A549 cells. Oncology reports 19 27499437
2015 Mechanism of Macrophage-Derived Chemokine/CCL22 Production by HaCaT Keratinocytes. Annals of dermatology 19 25834353

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