Accumulating evidence suggests that Foxp3+ cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprogrammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3+ cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage. We further demonstrated that the signal switch from IL-2 to ICOS during Treg activation induced Treg instability and reprogramming. By using a dual lineage tracing model, we demonstrated that effector Tregs can revert to central Tregs, and this reversion is associated with increasing Foxp3 stability in vivo.
This work was supported by National Natural Science Foundation of China Grants 31270959 and 31300750 and by National Key Basic Research and Development (973 Program of China) Grant 2012CB917102.
The raw RNA sequencing data presented in this article were submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE93856.
The online version of this article contains supplemental material.
- Received August 15, 2016.
- Accepted January 27, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.