Lineage stability and phenotypic plasticity of Foxp3⁺ regulatory T cells

Regulatory T (Treg) cells expressing the transcription factor forkhead box protein 3 (Foxp3) constitute a unique T-cell lineage committed to suppressive functions. While their differentiation state is remarkably stable in the face of various perturbations from the extracellular environment, they are able to adapt to diverse and fluctuating tissue environments by changing their phenotype. The lineage stability and phenotypic plasticity of Treg cells thus ensure the robustness of self-tolerance and tissue homeostasis. Recent studies have suggested, however, that Treg cells may retain lineage plasticity, the ability to switch their cell fate to various effector T-cell types under certain circumstances such as inflammation, a notion that remains highly contentious. While accumulating evidence indicates that some Treg cells can downregulate Foxp3 expression and/or acquire effector T-helper cell-like phenotypes, results from my laboratory have shown that Treg cells retain epigenetic memory of, and thus remain committed to, Foxp3 expression and suppressive functions despite such phenotypic plasticity. It has also become evident that Foxp3 can be promiscuously and transiently expressed in activated T cells. Here, I argue that the current controversy stems partly from the lack of the lineage specificity of Foxp3 expression and also from the confusion between phenotypic plasticity and lineage plasticity, and discuss implications of our findings in Treg cell fate determination and maintenance.