Journal article
Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis
- Abstract:
- 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<sup>+</sup> T cells reduced CCL3 secretion, boosted FoxP3<sup>+</sup> 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 20.5MB, Terms of use)
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- Publisher copy:
- 10.1038/s44161-023-00413-9
Authors
+ Netherlands Organisation for Health Research and Development
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- Funder identifier:
- https://ror.org/01yaj9a77
- Grant:
- 91619053
- Publisher:
- Springer Nature
- Journal:
- Nature Cardiovascular Research More from this journal
- Volume:
- 3
- Issue:
- 2
- Pages:
- 221-242
- Place of publication:
- England
- Publication date:
- 2024-01-22
- Acceptance date:
- 2023-12-14
- DOI:
- EISSN:
-
2731-0590
- Pmid:
-
39044999
- Language:
-
English
- Keywords:
- Pubs id:
-
1607505
- Local pid:
-
pubs:1607505
- Deposit date:
-
2025-05-22
- ARK identifier:
Terms of use
- Copyright holder:
- Döring et al
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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