Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model
Open accessAbstract
This report shows that interleukin (IL) 17–producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) γ and IL-4 for CCR6 expression. Forced expression of RORγt, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1β, IL-17, or tumor necrosis factor α, and is suppressed by IFN-γ or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.
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Th17 and Th22 subsets are pivotal to tackle extracellular pathogens, such as extracellular bacteria and fungi, and they both lack CXCR3 and express CCR6 and CCR4.
“Th17 and Th22 subsets are pivotal to tackle extracellular pathogens, such as extracellular bacteria and fungi, and they both lack CXCR3 and express CCR6 and CCR4 [152-154].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [153]
The Results and Discussion section, “Expression of CCR6 by Th17 cells” (page unavailable), reports that Th17 cells express CCR6. The cited paper does not establish the claim about Th22 cells, lack of CXCR3, expression of CCR4, or protection against extracellular bacteria and fungi. Its “Induction of CCR6 in Th17 cells in vitro” section also shows that CCR6 expression depends on the induction conditions. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTh17 cells preferentially utilize CCR6, also expressed by Treg cells, for migration to mucosal tissues enriched for CCL20.
“Th17 preferentially utilize CCR6, also expressed by Treg cells, for migration to mucosal tissues that are enriched for CCL20 [153].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [153]
The Results and Discussion sections on CCR6 expression and CCL20 production (pages not provided) report that Th17 cells express CCR6, some regulatory T cells also express it, and Th17 cells preferentially migrate in response to CCL20. The migration studied is to inflamed joints; our copy does not establish Th17 migration to CCL20-enriched mucosal tissues. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCCR6 and IL-23R have been linked to the pathogenicity of TH17 cells in autoimmune diseases.
“CCR6 and IL-23R have been linked to the pathogenicity of TH17 cells in autoimmune diseases (Hirota et al., 2007; Kohler et al., 2003; Langrish et al., 2005), such as multiple sclerosis, suggesting that the depression-associated hippocampal TH17 cells display CNS-directed pathogenic properties that may underlie a portion of their pro-depressive actions.”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Hirota et al., 2007
The Abstract (page unavailable) links CCR6-expressing Th17 cells to autoimmune arthritis and reports that blocking CCR6 substantially inhibits mouse arthritis. Our copy does not link IL-23R to Th17 pathogenicity or establish CCR6- or IL-23R-dependent pathogenicity in multiple sclerosis; those parts are not supported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRORγT promotes CCR6 expression.
“and RORγT promotes C-C chemokine receptor type 6 (CCR6) expression (Hirota et al., 2007).”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Hirota et al., 2007
CCR6 is a chemokine receptor that promotes the recruitment of pathogenic T cells to inflammatory sites.
“CCR6 is a chemokine receptor that promotes the recruitment of pathogenic T cells to inflammatory sites (Hirota et al., 2007; Kohler et al., 2003).”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Hirota et al., 2007
CCR6 is thought to promote TH17 cell recruitment to sites of inflammation.
“CCR6 is thought to promote TH17 cell recruitment to sites of inflammation (Hirota et al., 2007).”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Hirota et al., 2007
IL-21 promotes expression of IL-17 and RORγT.
“IL-21 also promotes expression of IL-17 and RORγT”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Hirota et al., 2007
In Results and Discussion, under “Induction of CCR6 in Th17 cells in vitro” (page unavailable), the paper says IL-6 and TGF-β can induce RORγt and reports that adding IL-21 did not elicit CCR6 expression. The searched passages do not say whether IL-21 promotes IL-17 or RORγt expression; the CCR6 result does not resolve that claim. (LLM, conf=0.76)
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- Authors
- Hirota, K., Yoshitomi, H., Hashimoto, M., Maeda, S., Teradaira, S., Sugimoto, N., Yamaguchi, T., Nomura, T., Ito, H., Nakamura, T., Sakaguchi, N., & Sakaguchi, S.
- Affiliations
- Kyoto University (JP)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2007-11-19
- Volume
- 204
- Issue
- 12
- Pages
- 2803-2812
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118525
- OpenAlex
- W2117340681
- Cited by
- 937
- References
- 30
- Citations by year
- 2026: 32 · 2025: 41 · 2024: 25 · 2023: 47 · 2022: 28 · 2021: 47 · 2020: 42 · 2019: 36 · 2018: 36 · 2017: 54 · 2016: 64 · 2015: 70 · 2014: 52 · 2013: 64 · 2012: 62
- FWCI
- 38.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- rheumatoid arthritis, Th17 cells, CCR6, CCL20, chemokine recruitment, synoviocytes, IL-17, joint inflammation, interleukin-1, interferon-gamma, IL-4, T cell differentiation, autoimmune arthritis
- MeSH terms
- Animals, Arthritis, Experimental, Arthritis, Rheumatoid, T-Lymphocytes, Helper-Inducer, Humans, Mice, Inbred BALB C, T-Lymphocytes, Transcription, Genetic, Macrophage Inflammatory Proteins, Oligonucleotide Array Sequence Analysis, Mice, Receptors, CCR6, Chemokine CCL20
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