Plasticity of Foxp3+ T Cells Reflects Promiscuous Foxp3 Expression in Conventional T Cells but Not Reprogramming of Regulatory T Cells

The emerging notion of environment-induced reprogramming of Foxp3+ regulatory T (Treg) cells into helper T (Th) cells remains controversial. By genetic fate mapping or adoptive transfers, we have identified a minor population of nonregulatory Foxp3+ T cells exhibiting promiscuous and transient Foxp3 expression, which gave rise to Foxp3− (“exFoxp3”) Th cells and selectively accumulated in inflammatory cytokine milieus or in lymphopenic environments including those in early ontogeny. In contrast, Treg cells did not undergo reprogramming under those conditions irrespective of their thymic or peripheral origins. Moreover, although a few Treg cells transiently lose Foxp3 expression, such “latent” Treg cells retained their memory and robustly re-expressed Foxp3 and suppressive function upon activation. This study establishes that Treg cells constitute a stable cell lineage, whose committed state in a changing environment is ensured by DNA demethylation of the Foxp3 locus irrespectively of ongoing Foxp3 expression. ► Foxp3+ T cells contain a minor nonregulatory population ► Th cells can be generated from Foxp3+ non-Treg cells but not Treg cells ► A few Treg cells transiently lose Foxp3 expression but retain its memory ► The committed state of Treg cells is ensured by TSDR demethylation