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

Cellular & Molecular Immunology (2018) | Download Citation

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 CD25hi 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.

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Acknowledgements

We thank M. Dayton, Li Sun, and Lisa Reid for technical assistance. This work was supported by the Rebecca L. Cooper Foundation, National Health and Medical Research Council of Australia (NHMRC) grants (1037321, 1080321, 1105209, 1143976), an NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and a Victorian State Government Operational Infrastructure Support grant. We acknowledge the Wurundjeri people of the Kulin nation as the traditional owners and custodians of the land on which most of the work was performed.

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Affiliations

  1. The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    • Yifan Zhan
    • , Ajithkumar Vasanthakumar
    • , Michael Chopin
    • , Stephen L. Nutt
    • , Axel Kallies
    •  & Andrew M. Lew
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia

    • Yifan Zhan
    • , Ajithkumar Vasanthakumar
    • , Michael Chopin
    • , Stephen L. Nutt
    • , Axel Kallies
    •  & Andrew M. Lew
  3. Guangzhou Institute of Paediatrics, Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, 510623, Guangzhou, Guangdong, China

    • Yifan Zhan
    •  & Yuxia Zhang
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia

    • Nancy Wang
    • , Ajithkumar Vasanthakumar
    • , Axel Kallies
    •  & Andrew M. Lew

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Correspondence to Yifan Zhan.

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https://doi.org/10.1038/s41423-018-0187-8