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Cell Mol Immunol. 2018 Dec 11. doi: 10.1038/s41423-018-0187-8. [Epub ahead of print]

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

Zhan Y1,2,3, Wang N4, Vasanthakumar A5,6,4, Zhang Y7, Chopin M5,6, Nutt SL5,6, Kallies A5,6,4, Lew AM5,6,4.

Author information

1
The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. zhan@wehi.edu.au.
2
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. zhan@wehi.edu.au.
3
Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, 510623, Guangzhou, Guangdong, China. zhan@wehi.edu.au.
4
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, 3010, Australia.
5
The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
6
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
7
Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, 510623, Guangzhou, Guangdong, China.

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.

PMID:
30538272
DOI:
10.1038/s41423-018-0187-8

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