Heterogeneity of natural Foxp3 + T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity

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Abstract
Natural regulatory T cells (Treg) represent a distinct lineage of T lymphocytes committed to suppressive functions, and expression of the transcription factor Foxp3 is thought to identify this lineage specifically. Here we report that, whereas the majority of natural CD4+Foxp3+ T cells maintain stable Foxp3 expression after adoptive transfer to lymphopenic or lymphoreplete recipients, a minor fraction enriched within the CD25− subset actually lose it. Some of those Foxp3− T cells adopt effector helper T cell (Th) functions, whereas some retain “memory” of previous Foxp3 expression, reacquiring Foxp3 upon activation. This minority “unstable” population exhibits flexible responses to cytokine signals, relying on transforming growth factor-β to maintain Foxp3 expression and responding to other cytokines by differentiating into effector Th in vitro. In contrast, CD4+Foxp3+CD25high T cells are resistant to such conversion to effector Th even after many rounds of cell division. These results demonstrate that natural Foxp3+ T cells are a heterogeneous population consisting of a committed Treg lineage and an uncommitted subpopulation with developmental plasticity.