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

Yvonne Döring; Emiel P.C. van der Vorst; Yi Yan; Carlos Neideck; Xavier Blanchet; Yvonne Jansen; Manuela Kemmerich; Soyolmaa Bayasgalan; Linsey J.F. Peters; Michael Hristov; Kiril Bidzhekov; Changjun Yin; Xi Zhang; Julian Leberzammer; Ya Li; Inhye Park; Maria Kral; Katrin Nitz; Laura Parma; Selin Gencer; Andreas J.R. Habenicht; Alexander Faussner; Daniel Teupser; Claudia Monaco; Lesca Holdt; Remco T.A. Megens; Dorothee Atzler; Donato Santovito; Philipp von Hundelshausen; Christian Weber

doi:10.1038/s44161-023-00413-9

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

Yvonne Döring^*, Emiel P.C. van der Vorst, Yi Yan, Carlos Neideck, Xavier Blanchet, Yvonne Jansen, Manuela Kemmerich, Soyolmaa Bayasgalan, Linsey J.F. Peters, Michael Hristov, Kiril Bidzhekov, Changjun Yin, Xi Zhang, Julian Leberzammer, Ya Li, Inhye Park, Maria Kral, Katrin Nitz, Laura Parma, Selin GencerAndreas J.R. Habenicht, Alexander Faussner, Daniel Teupser, Claudia Monaco, Lesca Holdt, Remco T.A. Megens, Dorothee Atzler, Donato Santovito, Philipp von Hundelshausen, Christian Weber^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	221-242
Number of pages	22
Journal	Nature cardiovascular research
Volume	3
Issue number	2
DOIs	https://doi.org/10.1038/s44161-023-00413-9
Publication status	Published - Feb 2024

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Döring, Y., van der Vorst, E. P. C., Yan, Y., Neideck, C., Blanchet, X., Jansen, Y., Kemmerich, M., Bayasgalan, S., Peters, L. J. F., Hristov, M., Bidzhekov, K., Yin, C., Zhang, X., Leberzammer, J., Li, Y., Park, I., Kral, M., Nitz, K., Parma, L., ... Weber, C. (2024). Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis. Nature cardiovascular research, 3(2), 221-242. https://doi.org/10.1038/s44161-023-00413-9

@article{706311067f6d4b959ec8f59d7f6f14bb,

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

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.",

author = "Yvonne D{\"o}ring and {van der Vorst}, {Emiel P.C.} and Yi Yan and Carlos Neideck and Xavier Blanchet and Yvonne Jansen and Manuela Kemmerich and Soyolmaa Bayasgalan and Peters, {Linsey J.F.} and Michael Hristov and Kiril Bidzhekov and Changjun Yin and Xi Zhang and Julian Leberzammer and Ya Li and Inhye Park and Maria Kral and Katrin Nitz and Laura Parma and Selin Gencer and Habenicht, {Andreas J.R.} and Alexander Faussner and Daniel Teupser and Claudia Monaco and Lesca Holdt and Megens, {Remco T.A.} and Dorothee Atzler and Donato Santovito and {von Hundelshausen}, Philipp and Christian Weber",

note = "Funding Information: We are indebted to A. Rot (Queen Mary University) for thoughtful discussions. We thank L. Saroyan, O. Schengel and staff at the animal facility (all LMU Munich) for excellent technical assistance. We thank S. Michaelides (LMU Munich) for generously providing Jurkat CCR4- and CCR8-transfectants, K. Pfeffer (Heinrich-Heine-Universit{\"a}t) for kindly providing Ccr4 mice and I. F{\"o}rster (Universit{\"a}t Bonn) for generously providing Ccl17 (GFP reporter knock-in) mice. This work was supported by Deutsche Forschungsgemeinschaft (DFG) SFB1123-A1/A10 to Y.D. and C.W., SFB1123-A2 to P.v.H., SFB1123-B1 to D.T. and L.H., SFB1123-Z1 to R.T.A.M., SFB1123-A5 to D.A., SFB1123-B5 to D.S. and 390857198-EXC 2145 to C.W.; by the European Research Council (AdG °692511 to C.W.); by the German Ministry of Education and Research (BMBF) and the German Center for Cardiovascular Research (DZHK) to Y.D., C.W., D.S. and E.P.C.v.d.V. (81X2600254, 81Z0600202 and 81Z0600203); by grants from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University and NWO-ZonMw Veni (91619053) to E.P.C.v.d.V.; by the DFG YI 133/3-5 and Friedrich-Baur-Stiftung 39/20 to C.Y.; by the DFG HA 1083/15-4, HA 1083/15-5 and ERA-CVD (PLAQUEFIGHT) 01KL1808 to A.J.R.H. and ERA-CVD (AtheroInside) 01KL1908 to R.T.A.M. The position of L.P. was kindly supported by DZHK (81X2600271). C.W. is van der Laar-Professor of Atherosclerosis. -/- e/e Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = feb,

doi = "10.1038/s44161-023-00413-9",

language = "English",

volume = "3",

pages = "221--242",

journal = "Nature cardiovascular research",

issn = "2731-0590",

publisher = "Nature Publishing Group",

number = "2",

}

Döring, Y, van der Vorst, EPC, Yan, Y, Neideck, C, Blanchet, X, Jansen, Y, Kemmerich, M, Bayasgalan, S, Peters, LJF, Hristov, M, Bidzhekov, K, Yin, C, Zhang, X, Leberzammer, J, Li, Y, Park, I, Kral, M, Nitz, K, Parma, L, Gencer, S, Habenicht, AJR, Faussner, A, Teupser, D, Monaco, C, Holdt, L, Megens, RTA, Atzler, D, Santovito, D, von Hundelshausen, P & Weber, C 2024, 'Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis', Nature cardiovascular research, vol. 3, no. 2, pp. 221-242. https://doi.org/10.1038/s44161-023-00413-9

TY - JOUR

T1 - Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis

AU - Döring, Yvonne

AU - van der Vorst, Emiel P.C.

AU - Yan, Yi

AU - Neideck, Carlos

AU - Blanchet, Xavier

AU - Jansen, Yvonne

AU - Kemmerich, Manuela

AU - Bayasgalan, Soyolmaa

AU - Peters, Linsey J.F.

AU - Hristov, Michael

AU - Bidzhekov, Kiril

AU - Yin, Changjun

AU - Zhang, Xi

AU - Leberzammer, Julian

AU - Li, Ya

AU - Park, Inhye

AU - Kral, Maria

AU - Nitz, Katrin

AU - Parma, Laura

AU - Gencer, Selin

AU - Habenicht, Andreas J.R.

AU - Faussner, Alexander

AU - Teupser, Daniel

AU - Monaco, Claudia

AU - Holdt, Lesca

AU - Megens, Remco T.A.

AU - Atzler, Dorothee

AU - Santovito, Donato

AU - von Hundelshausen, Philipp

AU - Weber, Christian

N1 - Funding Information: We are indebted to A. Rot (Queen Mary University) for thoughtful discussions. We thank L. Saroyan, O. Schengel and staff at the animal facility (all LMU Munich) for excellent technical assistance. We thank S. Michaelides (LMU Munich) for generously providing Jurkat CCR4- and CCR8-transfectants, K. Pfeffer (Heinrich-Heine-Universität) for kindly providing Ccr4 mice and I. Förster (Universität Bonn) for generously providing Ccl17 (GFP reporter knock-in) mice. This work was supported by Deutsche Forschungsgemeinschaft (DFG) SFB1123-A1/A10 to Y.D. and C.W., SFB1123-A2 to P.v.H., SFB1123-B1 to D.T. and L.H., SFB1123-Z1 to R.T.A.M., SFB1123-A5 to D.A., SFB1123-B5 to D.S. and 390857198-EXC 2145 to C.W.; by the European Research Council (AdG °692511 to C.W.); by the German Ministry of Education and Research (BMBF) and the German Center for Cardiovascular Research (DZHK) to Y.D., C.W., D.S. and E.P.C.v.d.V. (81X2600254, 81Z0600202 and 81Z0600203); by grants from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University and NWO-ZonMw Veni (91619053) to E.P.C.v.d.V.; by the DFG YI 133/3-5 and Friedrich-Baur-Stiftung 39/20 to C.Y.; by the DFG HA 1083/15-4, HA 1083/15-5 and ERA-CVD (PLAQUEFIGHT) 01KL1808 to A.J.R.H. and ERA-CVD (AtheroInside) 01KL1908 to R.T.A.M. The position of L.P. was kindly supported by DZHK (81X2600271). C.W. is van der Laar-Professor of Atherosclerosis. -/- e/e Publisher Copyright: © 2024, The Author(s).

PY - 2024/2

Y1 - 2024/2

N2 - 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.

AB - 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.

U2 - 10.1038/s44161-023-00413-9

DO - 10.1038/s44161-023-00413-9

M3 - Article

SN - 2731-0590

VL - 3

SP - 221

EP - 242

JO - Nature cardiovascular research

JF - Nature cardiovascular research

IS - 2

ER -

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

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