Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1345-50. doi: 10.1073/pnas.1524660113. Epub 2016 Jan 14.

Unstable FoxP3+ T regulatory cells in NZW mice.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
2
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 cbdm@hms.harvard.edu.

Abstract

Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.

KEYWORDS:

FoxP3 stability; Treg homeostasis; immunoregulation; inbred mice

PMID:
26768846
PMCID:
PMC4747713
DOI:
10.1073/pnas.1524660113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center