Döring, Yvonne; van der Vorst, Emiel P C; Yan, Yi; Neideck, Carlos; Blanchet, Xavier; Jansen, Yvonne; Kemmerich, Manuela; Bayasgalan, Soyolmaa; Peters, Linsey J F; Hristov, Michael; Bidzhekov, Kiril; Yin, Changjun; Zhang, Xi; Leberzammer, Julian; Li, Ya; Park, Inhye; Kral, Maria; Nitz, Katrin; Parma, Laura; Gencer, Selin; ... (2024). Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nature cardiovascular research, 3, pp. 221-242. Springer Nature 10.1038/s44161-023-00413-9
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CCL17 is produced by conventional dendritic cells (cDCs), signals through CCR4 on regulatory T cells (Tregs), and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that cDCs from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers, and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, while FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Tregs.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Angiology |
UniBE Contributor: |
Döring, Yvonne |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2731-0590 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
24 Jul 2024 15:23 |
Last Modified: |
24 Jul 2024 15:32 |
Publisher DOI: |
10.1038/s44161-023-00413-9 |
PubMed ID: |
39044999 |
Uncontrolled Keywords: |
atherosclerosis chemokine receptors chemokines regulatory T cells |
BORIS DOI: |
10.48350/199174 |
URI: |
https://boris.unibe.ch/id/eprint/199174 |
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