Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis

Doering, 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; Habenicht, Andreas J. R.; Faussner, Alexander; Teupser, Daniel; Monaco, Claudia; Holdt, Lesca; Megens, Remco T. A.; Atzler, Dorothee; Santovito, Donato; von Hundelshausen, Philipp und Weber, Christian (2024): Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. In: Nature Cardiovascular Research, Bd. 3, Nr. 2

Abstract

CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells 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, whereas 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 Treg cells. Doring, van der Vorst, Yan, Neideck et al. present a non-canonical chemokine pathway involving CCL17 signaling through CCR8, which induces CCL3 expression independent of CCR4 and suppresses the functions of atheroprotective Treg cells.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198