CCL17 signals through CCR8 to induce CCL3 expression and restrain atheroprotective Tregs

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Year of Publication:
2021
Faculty:
Faculty of Medicine

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Abstract:
The CC chemokine CCL17 plays diverse and seemingly opposing roles in immune homeostasis. CCL17 signals through CCR4 on regulatory T cells (Tregs) to promote their tissue localization. Also, CCL17 is produced by a subset of conventional dendritic cells (cDCs) and drives chronic inflammation and atherosclerosis by suppressing Treg functions through yet undefined mechanisms. We found that cDCs from CCL17-deficient mice displayed a pro-tolerogenic phenotype and transcriptomic profile that, surprisingly, was not phenocopied in mice lacking CCR4, thus indicating the involvement of an alternative pathway. We identified CCL3 as the only cytokine/chemokine decreased in plasma of CCL17-deficient mice. Correspondingly, CCL3 expression in cDCs and T cells was induced by CCL17 in the absence of CCR4. We provide several lines of evidence that CCR8 serves as a functional high-affinity CCL17 receptor expressed in CD4+ Tregs and that CCL17 signaling through CCR8 induces CCL3 expression in Tregs and suppresses their functions. Genetic deficiencies of CCL3, and of CCR8 in CD4+ T cells, as well as blockade of CCR8, reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, the administration of CCL3 exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, while FoxP3 expression was reduced. Collectively, our data establish a novel chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Tregs.
Keywords:
chemokines
chemokine receptors
atherosclerosis
regulatory T cells
DDC:
500 Natural sciences and mathematics
570 Life sciences
600 Technology, Medicine
610 Medical sciences and medicine

Identifier

DOI:
https://doi.org/10.5282/ubm/data.279
lmUB:
25710b70-214e-4185-9cd2-ba8b867d06a9

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