Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability

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.