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CCR2 enhances CD25 expression by FoxP3⁺ regulatory T cells and regulates their abundance independently of chemotaxis and CCR2⁺ myeloid cells.

ABSTRACT: A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3⁺ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT) and CCR2-/- strains. Thus, CCR2 deficiency resulted in profound loss of CD25^hi FoxP3⁺ Tregs in secondary lymphoid organs as well as in peripheral tissues. CCR2-/- Treg cells were also functionally inferior to WT cells. Interestingly, these changes to Treg cells did not depend on CCR2⁺ monocytes/moDCs (the cells where CCR2 receptors are most abundant). Rather, we demonstrated that CCR2 was required for TLR-stimulated, but not TCR- or IL-2-stimulated, CD25 upregulation on Treg cells. Thus, we propose that CCR2 signaling can increase the fitness of FoxP3⁺ Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.

SUBMITTER: Zhan Y

PROVIDER: S-EPMC7000403 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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CCR2 enhances CD25 expression by FoxP3+ regulatory T cells and regulates their abundance independently of chemotaxis and CCR2+ myeloid cells.

Zhan Yifan Y Wang Nancy N Vasanthakumar Ajithkumar A Zhang Yuxia Y Chopin Michael M Nutt Stephen L SL Kallies Axel A Lew Andrew M AM

Cellular & molecular immunology 20181211 2

A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3+ Treg cells. Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type (WT) and CCR2-/- strains. Thus, CCR2 deficiency resulted in profound loss of CD25hi FoxP3+ Tregs in secondary lymphoid o ...[more]

PMID: 30538272

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Project description:Systemic inflammation associated with major surgery rapidly accelerates atherosclerotic plaque progression in mice. Regulatory T cells (Tregs) have emerged as important modulators of atherogenesis. In coronary artery disease patients, low frequency of Tregs constitutes an independent risk factor for cardiovascular complications after non-cardiac surgery. In this exploratory analysis, we investigate whether preoperative Treg levels affect surgery-induced atherosclerotic lesion destabilization in a murine model of perioperative stress. After 9 weeks of high-cholesterol diet, atherosclerotic apolipoprotein E-deficient mice with modulated Treg levels were subjected to a 30-minute surgical procedure consisting of general isoflurane anesthesia, laparotomy and moderate blood loss. Controls underwent general anesthesia only. Brachiocephalic arteries were harvested 3 days after the intervention for histomorphological analyses of atherosclerotic plaques. Tregs were depleted by a single dose of anti-CD25 monoclonal antibody (mAb) administered 6 days prior to the intervention. Expansion of Tregs was induced by daily injections of IL-2/anti-IL-2 complex (IL-2C) on three consecutive days starting 3 days before surgery. Isotype-matched antibodies and PBS served as controls. Antibody-mediated modulation was Treg-specific. IL-2C treatment resulted in an eight-fold elevation of peripheral CD4+CD25+Foxp3+ Tregs compared to mice administered with anti-CD25 mAb. In mice treated with PBS and anti-CD25 mAb, surgical stress response caused a significant increase of atherosclerotic plaque necrosis (PBS: p < 0.001; anti-CD25 mAb: p = 0.037). Preoperative Treg expansion abrogated perioperative necrotic core formation (p = 0.556) and significantly enhanced postoperative atherosclerotic plaque stability compared to PBS-treated mice (p = 0.036). Postoperative plaque volume (p = 0.960), stenosis (p = 0.693), lesional collagen (p = 0.258), as well as the relative macrophage (p = 0.625) and smooth muscle cell content (p = 0.178) remained largely unaffected by preoperative Treg levels. In atherosclerotic mice, therapeutic expansion of Tregs prior to major surgery mitigates rapid effects on perioperative stress-driven atherosclerotic plaque destabilization. Future studies will show, whether short-term interventions modulating perioperative inflammation qualify for prevention of cardiovascular events associated with major non-cardiac surgery.

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Dataset Information

CCR2 enhances CD25 expression by FoxP3⁺ regulatory T cells and regulates their abundance independently of chemotaxis and CCR2⁺ myeloid cells.

Publications

CCR2 enhances CD25 expression by FoxP3<sup>+</sup> regulatory T cells and regulates their abundance independently of chemotaxis and CCR2<sup>+</sup> myeloid cells.

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