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

Natural regulatory T cells (T-reg) 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 (T-h) 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-beta to maintain Foxp3 expression and responding to other cytokines by differentiating into effector T-h in vitro. In contrast, CD4(+)Foxp3(+)CD25(high) 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. IMMUNOLOGY